Skip to content
2000
image of Coupling of SARS-CoV-2 to Amyloid Fibrils and Liquid-Liquid Phase Separation

Abstract

COVID-19 is a respiratory disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), but because the receptor protein of this virus can appear not only in the lungs and throat but also in various parts of the host's body, it causes different diseases. Recent observations have suggested that SARS-CoV-2 damages the central nervous system of patients in a manner similar to amyloid-associated neurodegenerative diseases such as Alzheimer's and Parkinson's. Neurodegenerative diseases are believed to be associated with the self-assembly of amyloid proteins and peptides. On the other hand, whole proteins or parts of them encoded by SARS-CoV-2 can form amyloid fibrils, which may play an important role in amyloid-related diseases. Motivated by this evidence, this mini-review discusses experimental and computational studies of SARS-CoV-2 proteins that can form amyloid aggregates. Liquid-Liquid Phase Separation (LLPS) is a dynamic and reversible process leading to the creation of membrane-less organelles within the cytoplasm, which is not bound by a membrane that concentrates specific types of biomolecules. These organelles play pivotal roles in cellular signaling, stress response, and the regulation of biomolecular condensates. Recently, LLPS of the Nucleocapsid (N) protein and SARS-CoV-2 RNA has been disclosed, but many questions about the phase separation mechanism and the formation of the virion core are still unclear. We summarize the results of this phenomenon and suggest potentially intriguing issues for future research.

Loading

Article metrics loading...

/content/journals/cpps/10.2174/0113892037354482250414045355
2025-05-08
2025-09-23
Loading full text...

Full text loading...

References

  1. Salamanna F. Maglio M. Landini M.P. Fini M. Body localization of ace-2: On the trail of the keyhole of SARS-COV-2. Front. Med. 2020 7 594495 10.3389/fmed.2020.594495 33344479
    [Google Scholar]
  2. Song E. Zhang C. Israelow B. Lu-Culligan A. Prado A.V. Skriabine S. Lu P. Weizman O.E. Liu F. Dai Y. Szigeti-Buck K. Yasumoto Y. Wang G. Castaldi C. Heltke J. Ng E. Wheeler J. Alfajaro M.M. Levavasseur E. Fontes B. Ravindra N.G. Dijk V.D. Mane S. Gunel M. Ring A. Kazmi S.A.J. Zhang K. Wilen C.B. Horvath T.L. Plu I. Haik S. Thomas J.L. Louvi A. Farhadian S.F. Huttner A. Seilhean D. Renier N. Bilguvar K. Iwasaki A. Neuroinvasion of SARS-COV-2 in human and mouse brain. J. Exp. Med. 2021 218 3 e20202135 10.1084/jem.20202135 33433624
    [Google Scholar]
  3. Matschke J. Lütgehetmann M. Hagel C. Sperhake J.P. Schröder A.S. Edler C. Mushumba H. Fitzek A. Allweiss L. Dandri M. Dottermusch M. Heinemann A. Pfefferle S. Schwabenland M. Magruder S.D. Bonn S. Prinz M. Gerloff C. Püschel K. Krasemann S. Aepfelbacher M. Glatzel M. Neuropathology of patients with COVID-19 in Germany: A post- mortem case series. Lancet Neurol. 2020 19 11 919 929 10.1016/S1474‑4422(20)30308‑2 33031735
    [Google Scholar]
  4. Frontera J.A. Yang D. Lewis A. Patel P. Medicherla C. Arena V. Fang T. Andino A. Snyder T. Madhavan M. Gratch D. Fuchs B. Dessy A. Canizares M. Jauregui R. Thomas B. Bauman K. Olivera A. Bhagat D. Sonson M. Park G. Stainman R. Sunwoo B. Talmasov D. Tamimi M. Zhu Y. Rosenthal J. Dygert L. Ristic M. Ishii H. Valdes E. Omari M. Gurin L. Huang J. Czeisler B.M. Kahn D.E. Zhou T. Lin J. Lord A.S. Melmed K. Meropol S. Troxel A.B. Petkova E. Wisniewski T. Balcer L. Morrison C. Yaghi S. Galetta S. A prospective study of long-term outcomes among hospitalized COVID-19 patients with and without neurological complications. J. Neurol. Sci. 2021 426 117486 10.1016/j.jns.2021.117486 34000678
    [Google Scholar]
  5. Ellul M.A. Benjamin L. Singh B. Lant S. Michael B.D. Easton A. Kneen R. Defres S. Sejvar J. Solomon T. Neurological associations of COVID-19. Lancet Neurol. 2020 19 9 767 783 10.1016/S1474‑4422(20)30221‑0 32622375
    [Google Scholar]
  6. Bonhenry D. Charnley M. Gonçalves J. Hammarström P. Heneka M.T. Itzhaki R. Lambert J.C. Mannan M. Baig A.M. Middeldorp J. Nyström S. Reynolds N.P. Stefanatou M. Berryman J.T. SARS-COV-2 infection as a cause of neurodegeneration. Lancet Neurol. 2024 23 6 562 563 10.1016/S1474‑4422(24)00178‑9 38760096
    [Google Scholar]
  7. Djordjevic J. Jones-Gotman M. Sousa D.K. Chertkow H. Olfaction in patients with mild cognitive impairment and Alzheimer’s disease. Neurobiol. Aging 2008 29 5 693 706 10.1016/j.neurobiolaging.2006.11.014 17207898
    [Google Scholar]
  8. Bhardwaj T. Gadhave K. Kapuganti S.K. Kumar P. Brotzakis Z.F. Saumya K.U. Nayak N. Kumar A. Joshi R. Mukherjee B. Bhardwaj A. Thakur K.G. Garg N. Vendruscolo M. Giri R. Amyloidogenic proteins in the SARS-CoV and SARS- COV-2 proteomes. Nat. Commun. 2023 14 1 945 10.1038/s41467‑023‑36234‑4 36806058
    [Google Scholar]
  9. Nguyen P.H. Ramamoorthy A. Sahoo B.R. Zheng J. Faller P. Straub J.E. Dominguez L. Shea J.E. Dokholyan N.V. Simone D.A. Ma B. Nussinov R. Najafi S. Ngo S.T. Loquet A. Chiricotto M. Ganguly P. McCarty J. Li M.S. Hall C. Wang Y. Miller Y. Melchionna S. Habenstein B. Timr S. Chen J. Hnath B. Strodel B. Kayed R. Lesné S. Wei G. Sterpone F. Doig A.J. Derreumaux P. Amyloid oligomers: A joint experimental/computational perspective on Alzheimer’s disease, Parkinson’s disease, type II diabetes, and amyotrophic lateral sclerosis. Chem. Rev. 2021 121 4 2545 2647 10.1021/acs.chemrev.0c01122 33543942
    [Google Scholar]
  10. Chiti F. Dobson C.M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 2006 75 1 333 366 10.1146/annurev.biochem.75.101304.123901 16756495
    [Google Scholar]
  11. Karran E. Strooper D.B. The amyloid hypothesis in Alzheimer disease: New insights from new therapeutics. Nat. Rev. Drug Discov. 2022 21 4 306 318 10.1038/s41573‑022‑00391‑w 35177833
    [Google Scholar]
  12. Calabresi P. Mechelli A. Natale G. Volpicelli-Daley L. Lazzaro D.G. Ghiglieri V. Alpha-synuclein in Parkinson’s disease and other synucleinopathies: From overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 2023 14 3 176 10.1038/s41419‑023‑05672‑9 36859484
    [Google Scholar]
  13. Rudnicka-Drożak E. Drożak P. Mizerski G. Zaborowski T. Ślusarska B. Nowicki G. Drożak M. Links between COVID-19 and Alzheimer’s disease—what do we already know? Int. J. Environ. Res. Public Health 2023 20 3 2146 10.3390/ijerph20032146 36767513
    [Google Scholar]
  14. Shajahan S.R. Kumar S. Ramli M.D.C. Unravelling the connection between COVID-19 and Alzheimer’s disease: A comprehensive review. Front. Aging Neurosci. 2024 15 1274452 10.3389/fnagi.2023.1274452 38259635
    [Google Scholar]
  15. Alberti S. Gladfelter A. Mittag T. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell 2019 176 3 419 434 10.1016/j.cell.2018.12.035 30682370
    [Google Scholar]
  16. Brocca S. Grandori R. Longhi S. Uversky V. Liquid–liquid phase separation by intrinsically disordered protein regions of viruses: Roles in viral life cycle and control of virus–host interactions. Int. J. Mol. Sci. 2020 21 23 9045 10.3390/ijms21239045 33260713
    [Google Scholar]
  17. Dignon G.L. Best R.B. Mittal J. Biomolecular phase separation: From molecular driving forces to macroscopic properties. Annu. Rev. Phys. Chem. 2020 71 1 53 75 10.1146/annurev‑physchem‑071819‑113553 32312191
    [Google Scholar]
  18. Das S. Lin Y.H. Vernon R.M. Forman-Kay J.D. Chan H.S. Comparative roles of charge, π, and hydrophobic interactions in sequence-dependent phase separation of intrinsically disordered proteins. Proc. Natl. Acad. Sci. USA 2020 117 46 28795 28805 10.1073/pnas.2008122117 33139563
    [Google Scholar]
  19. Wang B. Zhang L. Dai T. Qin Z. Lu H. Zhang L. Zhou F. Liquid–liquid phase separation in human health and diseases. Signal Transduct. Target. Ther. 2021 6 1 290 10.1038/s41392‑021‑00678‑1 34334791
    [Google Scholar]
  20. Banani S.F. Lee H.O. Hyman A.A. Rosen M.K. Biomolecular condensates: Organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 2017 18 5 285 298 10.1038/nrm.2017.7 28225081
    [Google Scholar]
  21. Chen H. Cui Y. Han X. Hu W. Sun M. Zhang Y. Wang P.H. Song G. Chen W. Lou J. Liquid–liquid phase separation by SARS-COV-2 nucleocapsid protein and RNA. Cell Res. 2020 30 12 1143 1145 10.1038/s41422‑020‑00408‑2 32901111
    [Google Scholar]
  22. Perdikari T.M. Murthy A.C. Ryan V.H. Watters S. Naik M.T. Fawzi N.L. SARS-CoV-2 nucleocapsid protein phase-separates with RNA and with human hnRNPs. EMBO J. 2020 39 24 e106478 10.15252/embj.2020106478 33200826
    [Google Scholar]
  23. Cubuk J. Alston J.J. Incicco J.J. Singh S. Stuchell-Brereton M.D. Ward M.D. Zimmerman M.I. Vithani N. Griffith D. Wagoner J.A. Bowman G.R. Hall K.B. Soranno A. Holehouse A.S. The SARS-COV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA. Nat. Commun. 2021 12 1 1936 10.1038/s41467‑021‑21953‑3 33782395
    [Google Scholar]
  24. Boeynaems S. Alberti S. Fawzi N.L. Mittag T. Polymenidou M. Rousseau F. Schymkowitz J. Shorter J. Wolozin B. Bosch D.V.L. Tompa P. Fuxreiter M. Protein phase separation: A new phase in cell biology. Trends Cell Biol. 2018 28 6 420 435 10.1016/j.tcb.2018.02.004 29602697
    [Google Scholar]
  25. Shin Y. Brangwynne C.P. Liquid phase condensation in cell physiology and disease. Science 2017 357 6357 eaaf4382 10.1126/science.aaf4382 28935776
    [Google Scholar]
  26. Hyman A.A. Weber C.A. Jülicher F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 2014 30 1 39 58 10.1146/annurev‑cellbio‑100913‑013325 25288112
    [Google Scholar]
  27. Kim D. Lee J.Y. Yang J.S. Kim J.W. Kim V.N. Chang H. The architecture of SARS-COV-2 transcriptome. Cell 2020 181 4 914 921.e10 10.1016/j.cell.2020.04.011 32330414
    [Google Scholar]
  28. Gordon D.E. Jang G.M. Bouhaddou M. Xu J. Obernier K. White K.M. O’Meara M.J. Rezelj V.V. Guo J.Z. Swaney D.L. Tummino T.A. Hüttenhain R. Kaake R.M. Richards A.L. Tutuncuoglu B. Foussard H. Batra J. Haas K. Modak M. Kim M. Haas P. Polacco B.J. Braberg H. Fabius J.M. Eckhardt M. Soucheray M. Bennett M.J. Cakir M. McGregor M.J. Li Q. Meyer B. Roesch F. Vallet T. Kain M.A. Miorin L. Moreno E. Naing Z.Z.C. Zhou Y. Peng S. Shi Y. Zhang Z. Shen W. Kirby I.T. Melnyk J.E. Chorba J.S. Lou K. Dai S.A. Barrio-Hernandez I. Memon D. Hernandez-Armenta C. Lyu J. Mathy C.J.P. Perica T. Pilla K.B. Ganesan S.J. Saltzberg D.J. Rakesh R. Liu X. Rosenthal S.B. Calviello L. Venkataramanan S. Liboy-Lugo J. Lin Y. Huang X.P. Liu Y. Wankowicz S.A. Bohn M. Safari M. Ugur F.S. Koh C. Savar N.S. Tran Q.D. Shengjuler D. Fletcher S.J. O’Neal M.C. Cai Y. Chang J.C.J. Broadhurst D.J. Klippsten S. Sharp P.P. Wenzell N.A. Kuzuoglu-Ozturk D. Wang H.Y. Trenker R. Young J.M. Cavero D.A. Hiatt J. Roth T.L. Rathore U. Subramanian A. Noack J. Hubert M. Stroud R.M. Frankel A.D. Rosenberg O.S. Verba K.A. Agard D.A. Ott M. Emerman M. Jura N. Zastrow V.M. Verdin E. Ashworth A. Schwartz O. d’Enfert C. Mukherjee S. Jacobson M. Malik H.S. Fujimori D.G. Ideker T. Craik C.S. Floor S.N. Fraser J.S. Gross J.D. Sali A. Roth B.L. Ruggero D. Taunton J. Kortemme T. Beltrao P. Vignuzzi M. García-Sastre A. Shokat K.M. Shoichet B.K. Krogan N.J. A SARS-COV-2 protein interaction map reveals targets for drug repurposing. Nature 2020 583 7816 459 468 10.1038/s41586‑020‑2286‑9 32353859
    [Google Scholar]
  29. Yang H. Rao Z. Structural biology of SARS-COV-2 and implications for therapeutic development. Nat. Rev. Microbiol. 2021 19 11 685 700 10.1038/s41579‑021‑00630‑8 34535791
    [Google Scholar]
  30. Nyström S. Hammarström P. Amyloidogenesis of SARS-COV-2 Spike Protein. J. Am. Chem. Soc. 2022 144 20 8945 8950 10.1021/jacs.2c03925 35579205
    [Google Scholar]
  31. Cao S. Song Z. Rong J. Andrikopoulos N. Liang X. Wang Y. Peng G. Ding F. Ke P.C. Spike protein fragments promote alzheimer’s amyloidogenesis. ACS Appl. Mater. Interfaces 2023 15 34 40317 40329 10.1021/acsami.3c09815 37585091
    [Google Scholar]
  32. Morozova O.V. Manuvera V.A. Barinov N.A. Subcheva E.N. Laktyushkin V.S. Ivanov D.A. Lazarev V.N. Klinov D.V. Self-assembling amyloid-like nanostructures from SARS- COV-2 S1, S2, RBD and N recombinant proteins. Arch. Biochem. Biophys. 2024 752 109843 10.1016/j.abb.2023.109843 38072298
    [Google Scholar]
  33. Ye Q. West A.M.V. Silletti S. Corbett K.D. Architecture and self-assembly of the SARS-CoV -2 nucleocapsid protein. Protein Sci. 2020 29 9 1890 1901 10.1002/pro.3909 32654247
    [Google Scholar]
  34. Tayeb-Fligelman E. Bowler J.T. Tai C.E. Sawaya M.R. Jiang Y.X. Garcia G. Jr Griner S.L. Cheng X. Salwinski L. Lutter L. Seidler P.M. Lu J. Rosenberg G.M. Hou K. Abskharon R. Pan H. Zee C.T. Boyer D.R. Li Y. Anderson D.H. Murray K.A. Falcon G. Cascio D. Saelices L. Damoiseaux R. Arumugaswami V. Guo F. Eisenberg D.S. Low complexity domains of the nucleocapsid protein of SARS-COV-2 form amyloid fibrils. Nat. Commun. 2023 14 1 2379 10.1038/s41467‑023‑37865‑3 37185252
    [Google Scholar]
  35. Nady A. Reichheld S.E. Sharpe S. An amyloidogenic fragment of the SARS CoV-2 envelope protein promotes serum amyloid A misfolding and fibrillization. bioRxiv 2024 1 9 10.1101/2024.04.25.591137
    [Google Scholar]
  36. Geng H. Subramanian S. Wu L. Bu H.F. Wang X. Du C. Plaen D.I.G. Tan X.D. SARS-COV-2 ORF8 forms intracellular aggregates and inhibits ifnγ-induced antiviral gene expression in human lung epithelial cells. Front. Immunol. 2021 12 679482 10.3389/fimmu.2021.679482 34177923
    [Google Scholar]
  37. Nishide G. Lim K. Tamura M. Kobayashi A. Zhao Q. Hazawa M. Ando T. Nishida N. Wong R.W. Nanoscopic elucidation of spontaneous self-assembly of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) open reading frame 6 (orf6) protein. J. Phys. Chem. Lett. 2023 14 38 8385 8396 10.1021/acs.jpclett.3c01440 37707320
    [Google Scholar]
  38. Charnley M. Islam S. Bindra G.K. Engwirda J. Ratcliffe J. Zhou J. Mezzenga R. Hulett M.D. Han K. Berryman J.T. Reynolds N.P. Neurotoxic amyloidogenic peptides in the proteome of SARS-COV-2: Potential implications for neurological symptoms in COVID-19. Nat. Commun. 2022 13 1 3387 10.1038/s41467‑022‑30932‑1 35697699
    [Google Scholar]
  39. Sanislav O. Tetaj R. Metali Ratcliffe J. Phillips W. Klein A.R. Sethi A. Zhou J. Mezzenga R. Saxer S.S. Charnley M. Annesley S.J. Reynolds N.P. Cell invasive amyloid assemblies from SARS-COV-2 peptides can form multiple polymorphs with varying neurotoxicity. Nanoscale 2024 16 42 19814 19827 10.1039/D4NR03030C 39363846
    [Google Scholar]
  40. Wölk C. Shen C. Hause G. Surya W. Torres J. Harvey R.D. Bello G. Membrane condensation and curvature induced by SARS-COV-2 envelope protein. Langmuir 2024 40 5 2646 2655 10.1021/acs.langmuir.3c03079 38258382
    [Google Scholar]
  41. Mehregan A. Pérez-Conesa S. Zhuang Y. Elbahnsi A. Pasini D. Lindahl E. Howard R.J. Ulens C. Delemotte L. Probing effects of the SARS-COV-2 E protein on membrane curvature and intracellular calcium. Biochim. Biophys. Acta Biomembr. 2022 1864 10 183994 10.1016/j.bbamem.2022.183994 35724739
    [Google Scholar]
  42. Bilog M. Cersosimo J. Vigil I. Desamero R.Z.B. Profit A.A. Effect of a SARS-COV-2 protein fragment on the amyloidogenic propensity of human islet amyloid polypeptide. ACS Chem. Neurosci. 2024 15 24 4431 4440 10.1021/acschemneuro.4c00473 39582236
    [Google Scholar]
  43. Lee J.G. Huang W. Lee H. Leemput D.V.J. Kane M.A. Han Z. Characterization of SARS-COV-2 proteins reveals Orf6 pathogenicity, subcellular localization, host interactions and attenuation by selinexor. Cell Biosci. 2021 11 1 58 10.1186/s13578‑021‑00568‑7 33766124
    [Google Scholar]
  44. Yoo T.Y. Mitchison T.J. Quantitative comparison of nuclear transport inhibition by SARS coronavirus ORF6 reveals the importance of oligomerization. Proc. Natl. Acad. Sci. USA 2024 121 4 e2307997121 10.1073/pnas.2307997121 38236733
    [Google Scholar]
  45. Bucciantini M. Rigacci S. Stefani M. Amyloid aggregation: Role of biological membranes and the aggregate–membrane system. J. Phys. Chem. Lett. 2014 5 3 517 527 10.1021/jz4024354 26276603
    [Google Scholar]
  46. Nguyen H.L. Linh H.Q. Krupa P. Penna L.G. Li M.S. Amyloid β dodecamer disrupts the neuronal membrane more strongly than the mature fibril: Understanding the role of oligomers in neurotoxicity. J. Phys. Chem. B 2022 126 20 3659 3672 10.1021/acs.jpcb.2c01769 35580354
    [Google Scholar]
  47. Jana A.K. Greenwood A.B. Hansmann U.H.E. Presence of a SARS-COV-2 protein enhances amyloid formation of serum amyloid A. J. Phys. Chem. B 2021 125 32 9155 9167 10.1021/acs.jpcb.1c04871 34370466
    [Google Scholar]
  48. Jana A.K. Lander C.W. Chesney A.D. Hansmann U.H.E. Effect of an amyloidogenic SARS-COV-2 protein fragment on α-synuclein monomers and fibrils. J. Phys. Chem. B 2022 126 20 3648 3658 10.1021/acs.jpcb.2c01254 35580331
    [Google Scholar]
  49. Islam S. Parves M.R. Islam M.J. Ali M.A. Efaz F.M. Hossain M.S. Ullah M.O. Halim M.A. Structural and functional effects of the L84S mutant in the SARS-COV-2 ORF8 dimer based on microsecond molecular dynamics study. J. Biomol. Struct. Dyn. 2023 1 18 10.1080/07391102.2023.2228919 37403295
    [Google Scholar]
  50. Gadhave K. Kumar P. Kumar A. Bhardwaj T. Garg N. Giri R. Conformational dynamics of 13 amino acids long NSP11 of SARS-COV-2 under membrane mimetics and different solvent conditions. Microb. Pathog. 2021 158 105041 10.1016/j.micpath.2021.105041 34119626
    [Google Scholar]
  51. Kumar A. Kumar P. Saumya K.U. Giri R. Investigating the conformational dynamics of SARS-COV-2 NSP6 protein with emphasis on non-transmembrane 91–112 & 231–290 regions. Microb. Pathog. 2021 161 Pt A 105236 10.1016/j.micpath.2021.105236 34648928
    [Google Scholar]
  52. Feng S. O’Brien A. Chen D.Y. Saeed M. Baker S.C. SARS-COV-2 nonstructural protein 6 from Alpha to Omicron: Evolution of a transmembrane protein. MBio 2023 14 4 e00688-23 10.1128/mbio.00688‑23 37477426
    [Google Scholar]
  53. Garmay Y. Rubel A. Egorov V. Peptide from NSP7 is able to form amyloid-like fibrils: Artifact or challenge to drug design? Biochim. Biophys. Acta. Proteins Proteomics 2023 1871 2 140884 10.1016/j.bbapap.2022.140884 36462605
    [Google Scholar]
  54. Wu Z. Zhang X. Huang Z. Ma K. SARS-COV-2 proteins interact with alpha synuclein and induce lewy body-like pathology in vitro. Int. J. Mol. Sci. 2022 23 6 3394 10.3390/ijms23063394 35328814
    [Google Scholar]
  55. Semerdzhiev S.A. Fakhree M.A.A. Segers-Nolten I. Blum C. Claessens M.M.A.E. Interactions between SARS-COV-2 n-protein and α-synuclein accelerate amyloid formation. ACS Chem. Neurosci. 2022 13 1 143 150 10.1021/acschemneuro.1c00666 34860005
    [Google Scholar]
  56. Semerdzhiev S.A. Segers-Nolten I. Schoot D.V.P. Blum C. Claessens M.M.A.E. SARS-COV-2 N-protein induces the formation of composite α-synuclein/N-protein fibrils that transform into a strain of α-synuclein fibrils. Nanoscale 2023 15 45 18337 18346 10.1039/D3NR03556E 37921451
    [Google Scholar]
  57. Philippens I.H.C.H.M. Böszörményi K.P. Wubben J.A.M. Fagrouch Z.C. Driel V.N. Mayenburg A.Q. Lozovagia D. Roos E. Schurink B. Bugiani M. Bontrop R.E. Middeldorp J. Bogers W.M. Geus-Oei D.L.F. Langermans J.A.M. Verschoor E.J. Stammes M.A. Verstrepen B.E. Brain inflammation and intracellular α-synuclein aggregates in macaques after SARS- COV-2 infection. Viruses 2022 14 4 776 10.3390/v14040776 35458506
    [Google Scholar]
  58. Chen J. Chen J. Lei Z. Zhang F. Zeng L.H. Wu X. Li S. Tan J. Amyloid precursor protein facilitates SARS-COV-2 virus entry into cells and enhances amyloid-β-associated pathology in APP/PS1 mouse model of Alzheimer’s disease. Transl. Psychiatry 2023 13 1 396 10.1038/s41398‑023‑02692‑z 38104129
    [Google Scholar]
  59. Camacho R.C. Alabed S. Zhou H. Chang S.L. Network meta- analysis on the changes of amyloid precursor protein expression following SARS-COV-2 infection. J. Neuroimmune Pharmacol. 2021 16 4 756 769 10.1007/s11481‑021‑10012‑9 34757528
    [Google Scholar]
  60. Li Y. Lu S. Gu J. Xia W. Zhang S. Zhang S. Wang Y. Zhang C. Sun Y. Lei J. Liu C. Su Z. Yang J. Peng X. Li D. SARS-COV-2 impairs the disassembly of stress granules and promotes als-associated amyloid aggregation. Protein Cell 2022 13 8 602 614 10.1007/s13238‑022‑00905‑7 35384603
    [Google Scholar]
  61. Ramani A. Müller L. Ostermann P.N. Gabriel E. Abida-Islam P. Müller-Schiffmann A. Mariappan A. Goureau O. Gruell H. Walker A. Andrée M. Hauka S. Houwaart T. Dilthey A. Wohlgemuth K. Omran H. Klein F. Wieczorek D. Adams O. Timm J. Korth C. Schaal H. Gopalakrishnan J. SARS -CoV-2 targets neurons of 3D human brain organoids. EMBO J. 2020 39 20 e106230 10.15252/embj.2020106230 32876341
    [Google Scholar]
  62. Eberle R.J. Coronado M.A. Gering I. Sommerhage S. Korostov K. Stefanski A. Stühler K. Kraemer-Schulien V. Blömeke L. Bannach O. Willbold D. Tau protein aggregation associated with SARS-COV-2 main protease. PLoS One 2023 18 8 e0288138 10.1371/journal.pone.0288138 37603556
    [Google Scholar]
  63. Zhang J. Mesias V.S.D. Chesney A.D. Anand V.K. Feng X. Hsing I.M. Hansmann U.H.E. Huang J. Differential effects of SARS-COV-2 amyloidogenic segments on the aggregation and toxicity of human islet amyloid polypeptide within membrane environments. Int. J. Biol. Macromol. 2024 283 Pt 4 137930 10.1016/j.ijbiomac.2024.137930 39579816
    [Google Scholar]
  64. Ghosh A. Pithadia A.S. Bhat J. Bera S. Midya A. Fierke C.A. Ramamoorthy A. Bhunia A. Self-assembly of a nine-residue amyloid-forming peptide fragment of SARS corona virus E-protein: Mechanism of self aggregation and amyloid-inhibition of hIAPP. Biochemistry 2015 54 13 2249 2261 10.1021/acs.biochem.5b00061 25785896
    [Google Scholar]
  65. Singh A.K. Khunti K. COVID-19 and diabetes. Annu. Rev. Med. 2022 73 1 129 147 10.1146/annurev‑med‑042220‑011857 34379444
    [Google Scholar]
  66. Zilio G. Masato A. Sandre M. Caregnato A. Moret F. Maciola A.K. Antonini A. Brucale M. Cendron L. Plotegher N. Bubacco L. SARS-COV-2-mimicking pseudoviral particles accelerate α-synuclein aggregation in vitro. ACS Chem. Neurosci. 2024 15 2 215 221 10.1021/acschemneuro.3c00468 38131609
    [Google Scholar]
  67. Mesias V.S.D. Zhu H. Tang X. Dai X. Liu W. Guo Y. Huang J. Moderate binding between two SARS-COV-2 protein segments and α-synuclein alters its toxic oligomerization propensity differently. J. Phys. Chem. Lett. 2022 13 45 10642 10648 10.1021/acs.jpclett.2c02278 36354180
    [Google Scholar]
  68. Wang J. Dai L. Deng M. Xiao T. Zhang Z. Zhang Z. SARS-COV-2 spike protein s1 domain accelerates α-synuclein phosphorylation and aggregation in cellular models of synucleinopathy. Mol. Neurobiol. 2024 61 4 2446 2458 10.1007/s12035‑023‑03726‑9 37897633
    [Google Scholar]
  69. Ma G. Zhang D.F. Zou Q.C. Xie X. Xu L. Feng X.L. Li X. Han J.B. Yu D. Deng Z.H. Qu W. Long J. Li M.H. Yao Y.G. Zeng J. SARS-COV-2 Spike protein S2 subunit modulates γ-secretase and enhances amyloid-β production in COVID-19 neuropathy. Cell Discov. 2022 8 1 99 10.1038/s41421‑022‑00458‑3 36180433
    [Google Scholar]
  70. Wang Y. Mandelkow E. Tau in physiology and pathology. Nat. Rev. Neurosci. 2016 17 1 22 35 10.1038/nrn.2015.1 26631930
    [Google Scholar]
  71. Yang J. Li Y. Wang S. Li H. Zhang L. Zhang H. Wang P.H. Zheng X. Yu X.F. Wei W. The SARS-COV-2 main protease induces neurotoxic TDP-43 cleavage and aggregates. Signal Transduct. Target. Ther. 2023 8 1 109 10.1038/s41392‑023‑01386‑8 36894543
    [Google Scholar]
  72. Jo M. Lee S. Jeon Y.M. Kim S. Kwon Y. Kim H.J. The role of TDP-43 propagation in neurodegenerative diseases: Integrating insights from clinical and experimental studies. Exp. Mol. Med. 2020 52 10 1652 1662 10.1038/s12276‑020‑00513‑7 33051572
    [Google Scholar]
  73. Arseni D. Chen R. Murzin A.G. Peak-Chew S.Y. Garringer H.J. Newell K.L. Kametani F. Robinson A.C. Vidal R. Ghetti B. Hasegawa M. Ryskeldi-Falcon B. TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP. Nature 2023 620 7975 898 903 10.1038/s41586‑023‑06405‑w 37532939
    [Google Scholar]
  74. Albornoz E.A. Amarilla A.A. Modhiran N. Parker S. Li X.X. Wijesundara D.K. Aguado J. Zamora A.P. McMillan C.L.D. Liang B. Peng N.Y.G. Sng J.D.J. Saima F.T. Fung J.N. Lee J.D. Paramitha D. Parry R. Avumegah M.S. Isaacs A. Lo M.W. Miranda-Chacon Z. Bradshaw D. Salinas-Rebolledo C. Rajapakse N.W. Wolvetang E.J. Munro T.P. Rojas-Fernandez A. Young P.R. Stacey K.J. Khromykh A.A. Chappell K.J. Watterson D. Woodruff T.M. SARS-COV-2 drives NLRP3 inflammasome activation in human microglia through spike protein. Mol. Psychiatry 2023 28 7 2878 2893 10.1038/s41380‑022‑01831‑0 36316366
    [Google Scholar]
  75. Gordon R. Albornoz E.A. Christie D.C. Langley M.R. Kumar V. Mantovani S. Robertson A.A.B. Butler M.S. Rowe D.B. O’Neill L.A. Kanthasamy A.G. Schroder K. Cooper M.A. Woodruff T.M. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci. Transl. Med. 2018 10 465 eaah4066 10.1126/scitranslmed.aah4066 30381407
    [Google Scholar]
  76. Chang M.H. Park J.H. Lee H.K. Choi J.Y. Koh Y.H. SARS-COV-2 spike protein 1 causes aggregation of α-synuclein via microglia-induced inflammation and production of mitochondrial ROS: Potential therapeutic applications of metformin. Biomedicines 2024 12 6 1223 10.3390/biomedicines12061223 38927430
    [Google Scholar]
  77. Pan P. Shen M. Yu Z. Ge W. Chen K. Tian M. Xiao F. Wang Z. Wang J. Jia Y. Wang W. Wan P. Zhang J. Chen W. Lei Z. Chen X. Luo Z. Zhang Q. Xu M. Li G. Li Y. Wu J. SARS-COV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. Nat. Commun. 2021 12 1 4664 10.1038/s41467‑021‑25015‑6 34341353
    [Google Scholar]
  78. Chiricosta L. Gugliandolo A. Mazzon E. SARS-COV-2 exacerbates beta-amyloid neurotoxicity, inflammation and oxidative stress in Alzheimer’s disease patients. Int. J. Mol. Sci. 2021 22 24 13603 10.3390/ijms222413603 34948400
    [Google Scholar]
  79. Lee B. Choi H.N. Che Y.H. Ko M. Seong H.M. Jo M.G. Kim S.H. Song C. Yoon S. Choi J. Kim J.H. Kim M. Lee M.Y. Park S.W. Kim H.J. Kim S.J. Moon D.S. Lee S. Park J.H. Yeo S.G. Everson R.G. Kim Y.J. Hong K.W. Roh I.S. Lyoo K.S. Kim Y.J. Yun S.P. SARS-COV-2 infection exacerbates the cellular pathology of Parkinson’s disease in human dopaminergic neurons and a mouse model. Cell Rep. Med. 2024 5 5 101570 10.1016/j.xcrm.2024.101570 38749422
    [Google Scholar]
  80. Gain C. Song S. Angtuaco T. Satta S. Kelesidis T. The role of oxidative stress in the pathogenesis of infections with coronaviruses. Front. Microbiol. 2023 13 1111930 10.3389/fmicb.2022.1111930 36713204
    [Google Scholar]
  81. Dey R. Bishayi B. Microglial inflammatory responses to sars-cov-2 infection: A comprehensive review. Cell. Mol. Neurobiol. 2024 44 1 2 10.1007/s10571‑023‑01444‑3 38099973
    [Google Scholar]
  82. Pomilio A.B. Vitale A.A. Lazarowski A.J. COVID-19 and alzheimer’s disease: Neuroinflammation, oxidative stress, ferroptosis, and mechanisms involved. Curr. Med. Chem. 2023 30 35 3993 4031 10.2174/0929867329666221003101548 36200215
    [Google Scholar]
  83. Hamad R.S. Al-kuraishy H.M. Alexiou A. Papadakis M. Ahmed E.A. Saad H.M. Batiha G.E.S. SARS-COV-2 infection and dysregulation of nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. Cell Stre. Chap. 2023 28 6 657 673 10.1007/s12192‑023‑01379‑0 37796433
    [Google Scholar]
  84. Chesney A.D. Maiti B. Hansmann U.H.E. Human amylin in the presence of SARS-COV-2 protein fragments. ACS Omega 2023 8 13 12501 12511 10.1021/acsomega.3c00621 37033831
    [Google Scholar]
  85. Chesney A.D. Maiti B. Hansmann U.H.E. SARS-COV-2 spike protein fragment eases amyloidogenesis of α-synuclein. J. Chem. Phys. 2023 159 1 015103 10.1063/5.0157331 37409768
    [Google Scholar]
  86. Coppola F. Pavlíček T. Král P. Coupling of SARS-COV-2 to Aβ amyloid fibrils. ACS Omega 2024 9 8 9295 9299 10.1021/acsomega.3c08481 38434865
    [Google Scholar]
  87. Idrees D. Kumar V. SARS-COV-2 spike protein interactions with amyloidogenic proteins: Potential clues to neurodegeneration. Biochem. Biophys. Res. Commun. 2021 554 94 98 10.1016/j.bbrc.2021.03.100 33789211
    [Google Scholar]
  88. Flores-León M. Lázaro D.F. Shvachiy L. Krisko A. Outeiro T.F. In silico analysis of the aggregation propensity of the SARS- COV-2 proteome: Insight into possible cellular pathologies. Biochim. Biophys. Acta. Prot. Prot. 2021 1869 10 140693 10.1016/j.bbapap.2021.140693 34237472
    [Google Scholar]
  89. Ribeiro-Filho H.V. Jara G.E. Batista F.A.H. Schleder G.R. Tonoli C.C.C. Soprano A.S. Guimarães S.L. Borges A.C. Cassago A. Bajgelman M.C. Marques R.E. Trivella D.B.B. Franchini K.G. Figueira A.C.M. Benedetti C.E. Lopes-de-Oliveira P.S. Structural dynamics of SARS-COV-2 nucleocapsid protein induced by RNA binding. PLOS Comput. Biol. 2022 18 5 e1010121 10.1371/journal.pcbi.1010121 35551296
    [Google Scholar]
  90. Caruso I.P. dos Santos Almeida V. Amaral D.M.J. Andrade D.G.C. Araújo D.G.R. Araújo D.T.S. Azevedo D.J.M. Barbosa G.M. Bartkevihi L. Bezerra P.R. dos Santos Cabral K.M. Lourenço D.I.O. Malizia-Motta C.L.F. Marques L.D.A. Mebus-Antunes N.C. Neves-Martins T.C. Sá D.J.M. Sanches K. Santana-Silva M.C. Vasconcelos A.A. da Silva Almeida M. Amorim D.G.C. Anobom C.D. Poian D.A.T. Gomes-Neto F. Pinheiro A.S. Almeida F.C.L. Insights into the specificity for the interaction of the promiscuous SARS-COV-2 nucleocapsid protein N-terminal domain with deoxyribonucleic acids. Int. J. Biol. Macromol. 2022 203 466 480 10.1016/j.ijbiomac.2022.01.121 35077748
    [Google Scholar]
  91. Caruso Í.P. Sanches K. Poian D.A.T. Pinheiro A.S. Almeida F.C.L. Dynamics of the SARS-COV-2 nucleoprotein N-terminal domain triggers RNA duplex destabilization. Biophys. J. 2021 120 14 2814 2827 10.1016/j.bpj.2021.06.003 34197802
    [Google Scholar]
  92. Khan A. Khan T.M. Saleem S. Junaid M. Ali A. Ali S.S. Khan M. Wei D.Q. Structural insights into the mechanism of RNA recognition by the N-terminal RNA-binding domain of the SARS-COV-2 nucleocapsid phosphoprotein. Comput. Struct. Biotechnol. J. 2020 18 2174 2184 10.1016/j.csbj.2020.08.006 32837710
    [Google Scholar]
  93. Sankararaman S. Hamre J. III Almsned F. Aljouie A. Bokhari Y. Alawwad M. Alomair L. Jafri M.S. Active site prediction of phosphorylated SARS-COV-2 N-Protein using molecular simulation. Inform. Med. Unlock. 2022 29 100889 10.1016/j.imu.2022.100889 35224174
    [Google Scholar]
  94. Muradyan N. Arakelov V. Sargsyan A. Paronyan A. Arakelov G. Nazaryan K. Impact of mutations on the stability of SARS-COV-2 nucleocapsid protein structure. Sci. Rep. 2024 14 1 5870 10.1038/s41598‑024‑55157‑8 38467657
    [Google Scholar]
  95. Różycki B. Boura E. Conformational ensemble of the full-length SARS-COV-2 nucleocapsid (N) protein based on molecular simulations and SAXS data. Biophys. Chem. 2022 288 106843 10.1016/j.bpc.2022.106843 35696898
    [Google Scholar]
  96. Gotor N.L. Armaos A. Calloni G. Burgas T.M. Vabulas R.M. Groot D.N.S. Tartaglia G.G. RNA-binding and prion domains: The Yin and Yang of phase separation. Nucleic Acids Res. 2020 48 17 9491 9504 10.1093/nar/gkaa681 32857852
    [Google Scholar]
  97. Ray S. Singh N. Kumar R. Patel K. Pandey S. Datta D. Mahato J. Panigrahi R. Navalkar A. Mehra S. Gadhe L. Chatterjee D. Sawner A.S. Maiti S. Bhatia S. Gerez J.A. Chowdhury A. Kumar A. Padinhateeri R. Riek R. Krishnamoorthy G. Maji S.K. α-Synuclein aggregation nucleates through liquid–liquid phase separation. Nat. Chem. 2020 12 8 705 716 10.1038/s41557‑020‑0465‑9 32514159
    [Google Scholar]
  98. Rai S.K. Savastano A. Singh P. Mukhopadhyay S. Zweckstetter M. Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease. Protein Sci. 2021 30 7 1294 1314 10.1002/pro.4093 33930220
    [Google Scholar]
  99. Carter G.C. Hsiung C.H. Simpson L. Yang H. Zhang X. N-terminal domain of TDP43 enhances liquid-liquid phase separation of globular proteins. J. Mol. Biol. 2021 433 10 166948 10.1016/j.jmb.2021.166948 33744316
    [Google Scholar]
  100. Lu S. Ye Q. Singh D. Cao Y. Diedrich J.K. Yates J.R. III Villa E. Cleveland D.W. Corbett K.D. The SARS-COV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein. Nat. Commun. 2021 12 1 502 10.1038/s41467‑020‑20768‑y 33479198
    [Google Scholar]
  101. Casasanta M.A. Jonaid G.M. Kaylor L. Luqiu W.Y. DiCecco L.A. Solares M.J. Berry S. Dearnaley W.J. Kelly D.F. Retracted: Structural insights of the SARS-COV-2 nucleocapsid protein: Implications for the inner-workings of rapid antigen tests. Microsc. Microanal. 2023 29 2 649 657 10.1093/micmic/ozac036 37749713
    [Google Scholar]
  102. Jack A. Ferro L.S. Trnka M.J. Wehri E. Nadgir A. Nguyenla X. Fox D. Costa K. Stanley S. Schaletzky J. Yildiz A. SARS-COV-2 nucleocapsid protein forms condensates with viral genomic RNA. PLoS Biol. 2021 19 10 e3001425 10.1371/journal.pbio.3001425 34634033
    [Google Scholar]
  103. Carlson C.R. Asfaha J.B. Ghent C.M. Howard C.J. Hartooni N. Safari M. Frankel A.D. Morgan D.O. Phosphoregulation of phase separation by the SARS-COV-2 n protein suggests a biophysical basis for its dual functions. Mol. Cell 2020 80 6 1092 1103.e4 10.1016/j.molcel.2020.11.025 33248025
    [Google Scholar]
  104. Sanders D.W. Kedersha N. Lee D.S.W. Strom A.R. Drake V. Riback J.A. Bracha D. Eeftens J.M. Iwanicki A. Wang A. Wei M.T. Whitney G. Lyons S.M. Anderson P. Jacobs W.M. Ivanov P. Brangwynne C.P. Competing protein-RNA interaction networks control multiphase intracellular organization. Cell 2020 181 2 306 324.e28 10.1016/j.cell.2020.03.050 32302570
    [Google Scholar]
  105. Gao T. Gao Y. Liu X. Nie Z. Sun H. Lin K. Peng H. Wang S. Identification and functional analysis of the SARS-COV-2 nucleocapsid protein. BMC Microbiol. 2021 21 1 58 10.1186/s12866‑021‑02107‑3 33618668
    [Google Scholar]
  106. Zhou R. Zeng R. Brunn V.A. Lei J. Structural characterization of the C-terminal domain of SARS-COV-2 nucleocapsid protein. Mol. Biomed. 2020 1 1 2 10.1186/s43556‑020‑00001‑4 34765991
    [Google Scholar]
  107. Wang S. Dai T. Qin Z. Pan T. Chu F. Lou L. Zhang L. Yang B. Huang H. Lu H. Zhou F. Targeting liquid–liquid phase separation of SARS-COV-2 nucleocapsid protein promotes innate antiviral immunity by elevating MAVS activity. Nat. Cell Biol. 2021 23 7 718 732 10.1038/s41556‑021‑00710‑0 34239064
    [Google Scholar]
  108. Wu C. Qavi A.J. Hachim A. Kavian N. Cole A.R. Moyle A.B. Wagner N.D. Sweeney-Gibbons J. Rohrs H.W. Gross M.L. Peiris J.S.M. Basler C.F. Farnsworth C.W. Valkenburg S.A. Amarasinghe G.K. Leung D.W. Characterization of SARS-COV-2 nucleocapsid protein reveals multiple functional consequences of the C-terminal domain. iScience 2021 24 6 102681 10.1016/j.isci.2021.102681 34095780
    [Google Scholar]
  109. Cubuk J. Alston J.J. Incicco J.J. Holehouse A.S. Hall K.B. Stuchell-Brereton M.D. Soranno A. The disordered N-terminal tail of SARS-COV-2 Nucleocapsid protein forms a dynamic complex with RNA. Nucleic Acids Res. 2024 52 5 2609 2624 10.1093/nar/gkad1215 38153183
    [Google Scholar]
  110. Dhamotharan K. Korn S.M. Wacker A. Becker M.A. Günther S. Schwalbe H. Schlundt A. A core network in the SARS-COV-2 nucleocapsid NTD mediates structural integrity and selective RNA-binding. Nat. Commun. 2024 15 1 10656 10.1038/s41467‑024‑55024‑0 39653699
    [Google Scholar]
  111. Cascarina S.M. Ross E.D. Phase separation by the SARS- COV-2 nucleocapsid protein: Consensus and open questions. J. Biol. Chem. 2022 298 3 101677 10.1016/j.jbc.2022.101677 35131265
    [Google Scholar]
  112. Zeng W. Liu G. Ma H. Zhao D. Yang Y. Liu M. Mohammed A. Zhao C. Yang Y. Xie J. Ding C. Ma X. Weng J. Gao Y. He H. Jin T. Biochemical characterization of SARS- COV-2 nucleocapsid protein. Biochem. Biophys. Res. Commun. 2020 527 3 618 623 10.1016/j.bbrc.2020.04.136 32416961
    [Google Scholar]
  113. Iserman C. Roden C.A. Boerneke M.A. Sealfon R.S.G. McLaughlin G.A. Jungreis I. Fritch E.J. Hou Y.J. Ekena J. Weidmann C.A. Theesfeld C.L. Kellis M. Troyanskaya O.G. Baric R.S. Sheahan T.P. Weeks K.M. Gladfelter A.S. Genomic RNA elements drive phase separation of the SARS-COV-2 nucleocapsid. Mol. Cell 2020 80 6 1078 1091.e6 10.1016/j.molcel.2020.11.041 33290746
    [Google Scholar]
  114. Yaron T.M. Heaton B.E. Levy T.M. Johnson J.L. Jordan T.X. Cohen B.M. Kerelsky A. Lin T.Y. Liberatore K.M. Bulaon D.K. Nest V.S.J. Koundouros N. Kastenhuber E.R. Mercadante M.N. Shobana-Ganesh K. He L. Schwartz R.E. Chen S. Weinstein H. Elemento O. Piskounova E. Nilsson- Payant B.E. Lee G. Trimarco J.D. Burke K.N. Hamele C.E. Chaparian R.R. Harding A.T. Tata A. Zhu X. Tata P.R. Smith C.M. Possemato A.P. Tkachev S.L. Hornbeck P.V. Beausoleil S.A. Anand S.K. Aguet F. Getz G. Davidson A.D. Heesom K. Kavanagh-Williamson M. Matthews D.A. tenOever B.R. Cantley L.C. Blenis J. Heaton N.S. Host protein kinases required for SARS-COV-2 nucleocapsid phosphorylation and viral replication. Sci. Signal. 2022 15 757 eabm0808 10.1126/scisignal.abm0808 36282911
    [Google Scholar]
  115. Botova M. Camacho-Zarco A.R. Tognetti J. Bessa L.M. Guseva S. Mikkola E. Salvi N. Maurin D. Herrmann T. Blackledge M. A specific phosphorylation-dependent conformational switch in SARS-COV-2 nucleocapsid protein inhibits RNA binding. Sci. Adv. 2024 10 31 eaax2323 10.1126/sciadv.aax2323 39093972
    [Google Scholar]
  116. Stuwe H. Reardon P.N. Yu Z. Shah S. Hughes K. Barbar E.J. Phosphorylation in the Ser/Arg-rich region of the nucleocapsid of SARS-COV-2 regulates phase separation by inhibiting self-association of a distant helix. J. Biol. Chem. 2024 300 6 107354 10.1016/j.jbc.2024.107354 38718862
    [Google Scholar]
  117. Chen A. Lupan A.M. Quek R.T. Stanciu S.G. Asaftei M. Stanciu G.A. Hardy K.S. Magalhães A.D.T. Silver P.A. Mitchison T.J. Salic A. A coronaviral pore-replicase complex links RNA synthesis and export from double-membrane vesicles. Sci. Adv. 2024 10 45 eadq9580 10.1126/sciadv.adq9580 39514670
    [Google Scholar]
  118. Zimmermann L. Zhao X. Makroczyova J. Wachsmuth-Melm M. Prasad V. Hensel Z. Bartenschlager R. Chlanda P. SARS- COV-2 NSP3 and NSP4 are minimal constituents of a pore spanning replication organelle. Nat. Commun. 2023 14 1 7894 10.1038/s41467‑023‑43666‑5 38036567
    [Google Scholar]
  119. Huang Y. Wang T. Zhong L. Zhang W. Zhang Y. Yu X. Yuan S. Ni T. Molecular architecture of coronavirus double-membrane vesicle pore complex. Nature 2024 633 8028 224 231 10.1038/s41586‑024‑07817‑y 39143215
    [Google Scholar]
  120. Ni X. Han Y. Zhou R. Zhou Y. Lei J. Structural insights into ribonucleoprotein dissociation by nucleocapsid protein interacting with non-structural protein 3 in SARS-COV-2. Commun. Biol. 2023 6 1 193 10.1038/s42003‑023‑04570‑2 36806252
    [Google Scholar]
  121. Bessa L.M. Guseva S. Camacho-Zarco A.R. Salvi N. Maurin D. Perez L.M. Botova M. Malki A. Nanao M. Jensen M.R. Ruigrok R.W.H. Blackledge M. The intrinsically disordered SARS-COV-2 nucleoprotein in dynamic complex with its viral partner NSP3a. Sci. Adv. 2022 8 3 eabm4034 10.1126/sciadv.abm4034 35044811
    [Google Scholar]
  122. Roingeard P. Eymieux S. Burlaud-Gaillard J. Hourioux C. Patient R. Blanchard E. The double-membrane vesicle (DMV): A virus-induced organelle dedicated to the replication of SARS- COV-2 and other positive-sense single-stranded RNA viruses. Cell. Mol. Life Sci. 2022 79 8 425 10.1007/s00018‑022‑04469‑x 35841484
    [Google Scholar]
  123. Wolff G. Limpens R.W.A.L. Zevenhoven-Dobbe J.C. Laugks U. Zheng S. Jong D.A.W.M. Koning R.I. Agard D.A. Grünewald K. Koster A.J. Snijder E.J. Bárcena M. A molecular pore spans the double membrane of the coronavirus replication organelle. Science 2020 369 6509 1395 1398 10.1126/science.abd3629 32763915
    [Google Scholar]
  124. Savastano A. Ibáñez de Opakua A. Rankovic M. Zweckstetter M. Nucleocapsid protein of SARS-COV-2 phase separates into RNA-rich polymerase-containing condensates. Nat. Commun. 2020 11 1 6041 10.1038/s41467‑020‑19843‑1 33247108
    [Google Scholar]
  125. Snijder E.J. Limpens R.W.A.L. Wilde D.A.H. Jong D.A.W.M. Zevenhoven-Dobbe J.C. Maier H.J. Faas F.F.G.A. Koster A.J. Bárcena M. A unifying structural and functional model of the coronavirus replication organelle: Tracking down RNA synthesis. PLoS Biol. 2020 18 6 e3000715 10.1371/journal.pbio.3000715 32511245
    [Google Scholar]
  126. Nikolic J. Bars L.R. Lama Z. Scrima N. Lagaudrière-Gesbert C. Gaudin Y. Blondel D. Negri bodies are viral factories with properties of liquid organelles. Nat. Commun. 2017 8 1 58 10.1038/s41467‑017‑00102‑9 28680096
    [Google Scholar]
  127. Wu H. Xing N. Meng K. Fu B. Xue W. Dong P. Tang W. Xiao Y. Liu G. Luo H. Nucleocapsid mutations R203K/G204R increase the infectivity, fitness, and virulence of SARS-COV-2. Cell. Host. Microbe. 2021 29 12 1788 1801.e6 10.1016/j.chom.2021.11.005
    [Google Scholar]
  128. Adly A.N. Bi M. Carlson C.R. Syed A.M. Ciling A. Doudna J.A. Cheng Y. Morgan D.O. Assembly of SARS-COV-2 ribonucleosomes by truncated N* variant of the nucleocapsid protein. J. Biol. Chem. 2023 299 12 105362 10.1016/j.jbc.2023.105362 37863261
    [Google Scholar]
  129. Mourier T. Shuaib M. Hala S. Mfarrej S. Alofi F. Naeem R. Alsomali A. Jorgensen D. Subudhi A.K. Rached B.F. Guan Q. Salunke R.P. Ooi A. Esau L. Douvropoulou O. Nugmanova R. Perumal S. Zhang H. Rajan I. Al-Omari A. Salih S. Shamsan A. Mutair A.A. Taha J. Alahmadi A. Khotani N. Alhamss A. Mahmoud A. Alquthami K. Dageeg A. Khogeer A. Hashem A.M. Moraga P. Volz E. Almontashiri N. Pain A. SARS-COV-2 genomes from Saudi Arabia implicate nucleocapsid mutations in host response and increased viral load. Nat. Commun. 2022 13 1 601 10.1038/s41467‑022‑28287‑8 35105893
    [Google Scholar]
  130. Zhao H. Wu D. Hassan S.A. Nguyen A. Chen J. Piszczek G. Schuck P. A conserved oligomerization domain in the disordered linker of coronavirus nucleocapsid proteins. Sci. Adv. 2023 9 14 eadg6473 10.1126/sciadv.adg6473 37018390
    [Google Scholar]
  131. Johnson B.A. Zhou Y. Lokugamage K.G. Vu M.N. Bopp N. Crocquet-Valdes P.A. Kalveram B. Schindewolf C. Liu Y. Scharton D. Plante J.A. Xie X. Aguilar P. Weaver S.C. Shi P.Y. Walker D.H. Routh A.L. Plante K.S. Menachery V.D. Nucleocapsid mutations in SARS-COV-2 augment replication and pathogenesis. PLoS Pathog. 2022 18 6 e1010627 10.1371/journal.ppat.1010627 35728038
    [Google Scholar]
  132. Carlson C.R. Adly A.N. Bi M. Howard C.J. Frost A. Cheng Y. Morgan D.O. Reconstitution of the SARS-COV-2 ribonucleosome provides insights into genomic RNA packaging and regulation by phosphorylation. J. Biol. Chem. 2022 298 11 102560 10.1016/j.jbc.2022.102560 36202211
    [Google Scholar]
  133. Klein S. Cortese M. Winter S.L. Wachsmuth-Melm M. Neufeldt C.J. Cerikan B. Stanifer M.L. Boulant S. Bartenschlager R. Chlanda P. SARS-COV-2 structure and replication characterized by in situ cryo-electron tomography. Nat. Commun. 2020 11 1 5885 10.1038/s41467‑020‑19619‑7 33208793
    [Google Scholar]
  134. Sun Z. Wang M. Wang W. Li D. Wang J. Sui G. Getah virus capsid protein undergoes co-condensation with viral genomic RNA to facilitate virion assembly. Int. J. Biol. Macromol. 2024 265 Pt 1 130847 10.1016/j.ijbiomac.2024.130847 38490381
    [Google Scholar]
  135. Kumar P. Kumar A. Garg N. Giri R. An insight into SARS- COV-2 membrane protein interaction with spike, envelope, and nucleocapsid proteins. J. Biomol. Struct. Dyn. 2023 41 3 1062 1071 10.1080/07391102.2021.2016490 34913847
    [Google Scholar]
  136. Nguyen H. Nguyen H.L. Lan P.D. Thai N.Q. Sikora M. Li M.S. Interaction of SARS-COV-2 with host cells and antibodies: Experiment and simulation. Chem. Soc. Rev. 2023 52 18 6497 6553 10.1039/D1CS01170G 37650302
    [Google Scholar]
  137. Al-Aly Z. Davis H. McCorkell L. Soares L. Wulf-Hanson S. Iwasaki A. Topol E.J. Long COVID science, research and policy. Nat. Med. 2024 30 8 2148 2164 10.1038/s41591‑024‑03173‑6 39122965
    [Google Scholar]
  138. Huang C. Feng F. Shi Y. Li W. Wang Z. Zhu Y. Yuan S. Hu D. Dai J. Jiang Q. Zhang R. Liu C. Zhang P. Protein kinase C inhibitors reduce SARS-COV-2 replication in cultured cells. Microbiol. Spectr. 2022 10 5 e01056-22 10.1128/spectrum.01056‑22 36000889
    [Google Scholar]
  139. Guo S. Lei X. Chang Y. Zhao J. Wang J. Dong X. Liu Q. Zhang Z. Wang L. Yi D. Ma L. Li Q. Zhang Y. Ding J. Liang C. Li X. Guo F. Wang J. Cen S. SARS-COV-2 hijacks cellular kinase CDK2 to promote viral RNA synthesis. Signal Transduct. Target. Ther. 2022 7 1 400 10.1038/s41392‑022‑01239‑w 36575184
    [Google Scholar]
  140. Yao H. Song Y. Chen Y. Wu N. Xu J. Sun C. Zhang J. Weng T. Zhang Z. Wu Z. Cheng L. Shi D. Lu X. Lei J. Crispin M. Shi Y. Li L. Li S. Molecular architecture of the SARS-COV-2 virus. Cell 2020 183 3 730 738.e13 10.1016/j.cell.2020.09.018 32979942
    [Google Scholar]
/content/journals/cpps/10.2174/0113892037354482250414045355
Loading
/content/journals/cpps/10.2174/0113892037354482250414045355
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test