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The SARS-CoV-2 main protease M^pro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells.

ABSTRACT: Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (M^pro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M^pro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the M^pro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.

SUBMITTER: Wenzel J

PROVIDER: S-EPMC8553622 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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The SARS-CoV-2 main protease M<sup>pro</sup> causes microvascular brain pathology by cleaving NEMO in brain endothelial cells.

Wenzel Jan J Lampe Josephine J Müller-Fielitz Helge H Schuster Raphael R Zille Marietta M Müller Kristin K Krohn Markus M Körbelin Jakob J Zhang Linlin L Özorhan Ümit Ü Neve Vanessa V Wagner Julian U G JUG Bojkova Denisa D Shumliakivska Mariana M Jiang Yun Y Fähnrich Anke A Ott Fabian F Sencio Valentin V Robil Cyril C Pfefferle Susanne S Sauve Florent F Coêlho Caio Fernando Ferreira CFF Franz Jonas J Spiecker Frauke F Lembrich Beate B Binder Sonja S Feller Nina N König Peter P Busch Hauke H Collin Ludovic L Villaseñor Roberto R Jöhren Olaf O Altmeppen Hermann C HC Pasparakis Manolis M Dimmeler Stefanie S Cinatl Jindrich J Püschel Klaus K Zelic Matija M Ofengeim Dimitry D Stadelmann Christine C Trottein François F Nogueiras Ruben R Hilgenfeld Rolf R Glatzel Markus M Prevot Vincent V Schwaninger Markus M

Nature neuroscience 20211021 11

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capilla ...[more]

PMID: 34675436

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Project description:UnlabelledPorcine epidemic diarrhea virus (PEDV) is an enteropathogenic coronavirus causing lethal watery diarrhea in piglets. Since 2010, a PEDV variant has spread rapidly in China, and it emerged in the United States in 2013, posing significant economic and public health concerns. The ability to circumvent the interferon (IFN) antiviral response, as suggested for PEDV, promotes viral survival and regulates pathogenesis of PEDV infections, but the underlying mechanisms remain obscure. Here, we show that PEDV-encoded 3C-like protease, nsp5, is an IFN antagonist that proteolytically cleaves the nuclear transcription factor kappa B (NF-κB) essential modulator (NEMO), an essential adaptor bridging interferon-regulatory factor and NF-κB activation. NEMO is cleaved at glutamine 231 (Q231) by PEDV, and this cleavage impaired the ability of NEMO to activate downstream IFN production and to act as a signaling adaptor of the RIG-I/MDA5 pathway. Mutations specifically disrupting the cysteine protease activity of PEDV nsp5 abrogated NEMO cleavage and the inhibition of IFN induction. Structural analysis suggests that several key residues outside the catalytic sites of PEDV nsp5 probably impact NEMO cleavage by modulating potential interactions of nsp5 with their substrates. These data show that PEDV nsp5 disrupts type I IFN signaling by cleaving NEMO. Previously, we and others demonstrated that NEMO is also cleaved by 3C or 3C-like proteinases of picornavirus and artertivirus. Thus, NEMO probably represents a prime target for 3C or 3C-like proteinases of different viruses.ImportanceThe continued emergence and reemergence of porcine epidemic diarrhea virus (PEDV) underscore the importance of studying how this virus manipulates the immune responses of its hosts. During coevolution with its hosts, PEDV has acquired mechanisms to subvert host innate immune responses for its survival advantage. At least two proteins encoded by PEDV have been identified as interferon (IFN) antagonists, papain-like protease (PLP) and N protein. Here, we report that the PEDV nsp5 gene, which encodes the 3C-like protease of PEDV, is another IFN antagonist. Mechanistically, the cysteine protease activity of PEDV nsp5 mediates proteolysis of NEMO, the key adaptor for IFN synthesis, and NEMO is cleaved at glutamine 231 (Q231). The new molecular details and determinants impacting NEMO scission by PEDV nsp5 delineated in this study are fundamental to our understanding of critical virus-host interactions that determine PEDV pathogenesis.

Dataset Information

The SARS-CoV-2 main protease M^pro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells.

Publications

The SARS-CoV-2 main protease M<sup>pro</sup> causes microvascular brain pathology by cleaving NEMO in brain endothelial cells.

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Dataset Information

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells.

Publications

The SARS-CoV-2 main protease M<sup>pro</sup> causes microvascular brain pathology by cleaving NEMO in brain endothelial cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The SARS-CoV-2 main protease M^pro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells.