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SARS-CoV-2 Nsp3 interactome in Caco-2 cells during authentic infection

ABSTRACT: The nonstructural protein 3 (Nsp3) of SARS-CoV-2 is a large, multi-domain protein that localizes to double-membrane vesicles (DMVs), the physical site where SARS-CoV-2 (and other coronaviruses) replicate inside mammalian cells. One of the domains of Nsp3 is PLpro (papain-like protease), which harbors enzymatic activities (i.e., protease, deubiquitinase, and deISGylase). To identify human cellular proteins that bind Nsp3, we performed LC-MS/MS analysis of affinity-purified Nsp3 from SARS‑CoV‑2–infected Caco-2 (human intestinal epithelial) cells. This dataset identified numerous Nsp3-interacting proteins that play key roles in various host cellular processes, including metabolism and innate immunity.

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ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Junji Zhu

LAB HEAD: Michaela Gack

PROVIDER: PXD068796 | Pride | 2026-05-05

REPOSITORIES: Pride

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Project description:Human coronaviruses have become an increasing threat to global health; three highly pathogenic strains have emerged since the early 2000s, including most recently SARS-CoV-2, the cause of COVID-19. A better understanding of the molecular mechanisms of coronavirus pathogenesis is needed, including how these highly virulent strains differ from those that cause milder, common-cold like disease. While significant progress has been made in understanding how SARS-CoV-2 proteins interact with the host cell, non-structural protein 3 (nsp3) has largely been omitted from the analyses. Nsp3 is a viral protease with important roles in viral protein biogenesis, replication complex formation, and modulation of host ubiquitinylation and ISGylation. Herein, we use affinity purification-mass spectrometry to study the host-viral protein-protein interactome of nsp3 from five coronavirus strains: pathogenic strains SARS-CoV-2, SARS-CoV, and MERS-CoV, and endemic common-cold strains hCoV-229E and hCoV-OC43. We divide each nsp3 into three fragments and use tandem mass tag technology to directly compare the interactors across the five strains for each fragment. We find that that few interactors are common across all variants for a particular fragment, but we identify shared patterns between select variants, such as ribosomal proteins enriched in the N-terminal fragment (nsp3.1) analysis for SARS-CoV-2 and SARS-CoV. We also identify unique biological processes enriched for individual homologs, for instance nuclear protein important for the middle fragment of hCoV-229E, as well as ribosome biogenesis of the MERS nsp3.1 homolog. Lastly, we further investigate the interaction of the SARS-CoV-2 nsp3.1 N-terminal fragment with ATF6, a regulator of the unfolded protein response. We show that SARS-CoV-2 nsp3.1 directly binds to ATF6 and can suppress the ATF6 stress response. Characterizing the host interactions of nsp3 widens our understanding of how coronaviruses co-opt cellular pathways and presents new avenues for host-targeted antiviral therapeutics.

			Action	DRS
	Mock_Area1.d.zip	Other
	Mock_Area1.mzML	Mzml
	Mock_Area1.pepXML	Pepxml
	Mock_Area10.d.zip	Other
	Mock_Area10.mzML	Mzml

Dataset Information

SARS-CoV-2 Nsp3 interactome in Caco-2 cells during authentic infection

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