Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils

Tayeb-Fligelman, Einav; Bowler, Jeannette T.; Tai, Christen; Sawaya, M.R.; Jiang, Yi; García, Gustavo; Griner, Sarah L.; Cheng, Xinyi; Salwiński, Łukasz; Lutter, Liisa; Seidler, Paul M.; Lu, Jiahui; Rosenberg, Gregory M.; Hou, Ke; Abskharon, Romany; Pan, Hope; Zee, Chih-Te; Boyer, David R.; Li, Yan; Anderson, D.; Murray, Kevin; Falcon, Genesis; Cascio, Duilio; Saelices, Lorena; Damoiseaux, Robert; Arumugaswami, Vaithilingaraja; Guo, Feng; Eisenberg, David S.

doi:10.1038/s41467-023-37865-3

Cited by 14 publications

(25 citation statements)

References 93 publications

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“…481 Apart from cancer, lethal viral infections such as SARS-CoV-2 (the severe acute respiratory syndrome coronavirus 2) have also shown its potential connection with LLPS and amyloid aggregation as the nucleocapsid protein of the virus contains LCD promoting both events. 482,483 Similarly, a metabolic disorder such as type II diabetes has also been shown to be affected by LLPS-mediated aberrant aggregation as insulin-derived peptides and islet amyloid polypeptide (IAPP) can promote the amyloidogenic pathway from phase separation. 484,485 Since the LLPS phenomenon is ubiquitous in cell physiology, the underlying pathological risk of cellular mis-regulation is an unavoidable consequence leading to diverse disease pathogenesis.…”

Section: Llps: a Generic Nucleation Mechanism In The Amyloid Aggregat...mentioning

confidence: 99%

Protein misfolding and amyloid nucleation through liquid–liquid phase separation

Mukherjee,

Poudyal,

Dave

et al. 2024

Chem. Soc. Rev.

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Section: Llps: a Generic Nucleation Mechanism In The Amyloid Aggregat...mentioning

confidence: 99%

Protein misfolding and amyloid nucleation through liquid–liquid phase separation

Mukherjee,

Poudyal,

Dave

et al. 2024

Chem. Soc. Rev.

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“…NP consists of two structured domains, the N-terminal domain (NTD), and the C-terminal domain (CTD), which are connected by a linker. The CTD serves as a dimerization domain of NP, which in turn has also been reported to form higher order oligomers via its linker region (17), as well as via its C-terminal helix (18). Many previous studies have demonstrated the importance of NTD in association with viral RNA and described the atomic details of these interactions (19).…”

Section: Introductionmentioning

confidence: 99%

Binding of SARS-CoV-2 nucleocapsid protein to uninfected epithelial cells induces antibody-mediated complement deposition

Fahoum,

Billan,

Varga

et al. 2024

Preprint

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SARS-CoV-2 infection triggers strong antibody response toward Nucleocapsid-Protein (NP), suggesting extracellular presence beyond its intra-virion RNA binding. Interestingly, NP was found to decorate infected and proximal uninfected cell-surfaces. Here, we propose a new mechanism through which extracellular NP on uninfected cells contributes to COVID-19 pathogenicity. We show that NP binds to cell-surface sulfated linear-glycosaminoglycans by spatial rearrangement of its RNA-binding sites facilitated by the flexible, positively charged, linker. Coating of uninfected lung-derived cells with purified NP attracted anti-NP-IgG from lung fluids and sera collected from COVID-19 patients. The magnitude of this immune recognition was significantly elevated in moderate compared to mild COVID-19 cases. Importantly, binding of anti-NP-IgG present in sera generated clusters that triggered C3b deposition by the classical complement pathway. Heparin analog enoxaparin outcompeted NP-binding, rescuing cells from anti-NP IgG-mediated complement deposition. Our findings unveil how extracellular NP may exacerbate COVID-19 tissue damage, and suggest leads for preventative therapy.

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“…It was recently discovered that the SARS-CoV-2 virus proteome includes different sequences of amyloid-forming proteins [ 4 , 29 , 30 ]. It is assumed that amyloid-forming proteins from the SARS-CoV-2 virus may be involved in the development of neurological symptoms in COVID-19-infected patients [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Promising Strategies to Reduce the SARS-CoV-2 Amyloid Deposition in the Brain and Prevent COVID-19-Exacerbated Dementia and Alzheimer’s Disease

Navolokin,

Adushkina,

Zlatogorskaya

et al. 2024

Pharmaceuticals

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The COVID-19 pandemic, caused by infection with the SARS-CoV-2 virus, is associated with cognitive impairment and Alzheimer’s disease (AD) progression. Once it enters the brain, the SARS-CoV-2 virus stimulates accumulation of amyloids in the brain that are highly toxic to neural cells. These amyloids may trigger neurological symptoms in COVID-19. The meningeal lymphatic vessels (MLVs) play an important role in removal of toxins and mediate viral drainage from the brain. MLVs are considered a promising target to prevent COVID-19-exacerbated dementia. However, there are limited methods for augmentation of MLV function. This review highlights new discoveries in the field of COVID-19-mediated amyloid accumulation in the brain associated with the neurological symptoms and the development of promising strategies to stimulate clearance of amyloids from the brain through lymphatic and other pathways. These strategies are based on innovative methods of treating brain dysfunction induced by COVID-19 infection, including the use of photobiomodulation, plasmalogens, and medicinal herbs, which offer hope for addressing the challenges posed by the SARS-CoV-2 virus.

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Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils

Cited by 14 publications

References 93 publications

Protein misfolding and amyloid nucleation through liquid–liquid phase separation

Protein misfolding and amyloid nucleation through liquid–liquid phase separation

Binding of SARS-CoV-2 nucleocapsid protein to uninfected epithelial cells induces antibody-mediated complement deposition

Promising Strategies to Reduce the SARS-CoV-2 Amyloid Deposition in the Brain and Prevent COVID-19-Exacerbated Dementia and Alzheimer’s Disease

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