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Interaction Landscape of Ancestral and Variants SCoV2-Human Protein Assemblies Revealed in Distinct Organs and Body Fluids of COVID-19 Patients

ABSTRACT: Knowledge of SARS-CoV2 (SCoV2) human protein-protein interactions (PPIs), and host response to viral infection is key to designing new antivirals to thwart COVID-19. Yet, it remains unclear how ancestral and variants SCoV2 detected in many body parts or fluids remodel virus-host protein assemblies. Here, we performed >600 affinity-purifications by tagging and expressing 28 SCoV2 proteins, and spike protein from ancestral and four variants in eight cell lines, derived from five mammalian organs or biofluid, and identified human proteins associated with each viral protein by mass spectrometry (MS). The ensuing high-quality and previously unreported SCoV2-human PPIs were largely organ or variant-specific. Besides confirming these PPIs in COVID-19 patients saliva by MS-based co-fractionation, host PPIs were altered between variants and ancestral SCoV2. We show SCoV2 NSP3 papain-like protease is a secreted protein that binds with fibrinogen to promote abnormal blood clots, and with interferon-induced proteins to evade host innate immunity. Deep-learning aided design of peptide inhibitors impeded SCoV2 and variants replication in human liver cells, and restored PPI changes by the virus to healthy state. Our results unveil new mechanisms for human-ancestral or variants SCoV2 PPIs in various organs or biofluids, offering potential host therapeutic targets and SCoV2 inhibitors for antiviral development.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Severe Acute Respiratory Syndrome Coronavirus 2 (ncbitaxon:2697049) Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Dr. Mohan Babu

PROVIDER: MSV000096435 | MassIVE | Sat Nov 16 12:15:00 GMT 2024

REPOSITORIES: MassIVE

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Project description:SARS-CoV-2 virus and its variants have proven to be a threat to global health, in part due to their capacity for rapid evolution. SARS-CoV-2 variants that emerged throughout the COVID-19 pandemic exhibited variations in virulence, leading to diminished vaccine protection and modulating disease severity. Research efforts have identified the molecular changes resulting from structural protein variants of SARS-CoV-2, particularly in Spike, that have enhanced infectivity. Yet, investigating variants of nonstructural proteins is equally critical to understand viral evolution and their role in manipulating protein-protein interactions within a host. This study focuses on nonstructural protein 3 (nsp3), a viral papain-like protease (PLpro) critical for viral polyprotein cleavage, which is also implicated in host de-ubiquitylation, ISGylation, and formation of double-membrane vesicles. Using affinity-purification mass spectrometry (AP-MS), we identify differential protein interactions caused by mutations in nsp3. Included are variants identified between 2019-2024: Alpha 20I, Beta20H, Delta21I, Delta21J, Gamma20J, Kappa21B, Lambda21G, Omicron21K, Omicron21L. A small set of amino acid substitutions in the cytosolic fragment and N-terminal region of nsp3 (nsp3.1) could be traced to increased interactions with RNA binding proteins, which are vital in viral replication. Nsp3.1 variants from Omicron 21K and 21L exhibit distinct patterns of host interactor enrichment, setting them apart from five other variants. In contrast, variants of the central region of nsp3 (nsp3.2) containing the PL2pro domain were found to share interactions with protein quality control machinery, including ER-associated degradation (ERAD). In this construct, shared trends in interactor enrichment are observed between Omicron21K and Delta21I, distinguishing them from three other variants. Our study highlights that even a small number of amino acid substitutions can significantly alter the interaction partners. Our study provides a roadmap to track the interaction changes driven by SARS-CoV-2 variant evolution, which is essential for elucidating the ongoing evolutionary arms race between the host and virus.

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Interaction Landscape of Ancestral and Variants SCoV2-Human Protein Assemblies Revealed in Distinct Organs and Body Fluids of COVID-19 Patients

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