Comparative Proteomics Reveals Strain-Specific β-TrCP Degradation via Rotavirus NSP1 Hijacking a Host Cullin-3-Rbx1 Complex

Siyuan Ding, Nancie Mooney, Bin Li, Marcus R. Kelly, Ningguo Feng, Alexander V. Loktev, Adrish Sen, John T. Patton, Peter K. Jackson, Harry B. Greenberg

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26 Scopus citations

Abstract

Rotaviruses (RVs) are the leading cause of severe gastroenteritis in young children, accounting for half a million deaths annually worldwide. RV encodes non-structural protein 1 (NSP1), a well-characterized interferon (IFN) antagonist, which facilitates virus replication by mediating the degradation of host antiviral factors including IRF3 and β-TrCP. Here, we utilized six human and animal RV NSP1s as baits and performed tandem-affinity purification coupled with high-resolution mass spectrometry to comprehensively characterize NSP1-host protein interaction network. Multiple Cullin-RING ubiquitin ligase (CRL) complexes were identified. Importantly, inhibition of cullin-3 (Cul3) or RING-box protein 1 (Rbx1), by siRNA silencing or chemical perturbation, significantly impairs strain-specific NSP1-mediated β-TrCP degradation. Mechanistically, we demonstrate that NSP1 localizes to the Golgi with the host Cul3-Rbx1 CRL complex, which targets β-TrCP and NSP1 for co-destruction at the proteasome. Our study uncovers a novel mechanism that RV employs to promote β-TrCP turnover and provides molecular insights into virus-mediated innate immunity inhibition.

Original languageEnglish
Article numbere1005929
JournalPLoS pathogens
Volume12
Issue number10
DOIs
StatePublished - Oct 2016

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    Ding, S., Mooney, N., Li, B., Kelly, M. R., Feng, N., Loktev, A. V., Sen, A., Patton, J. T., Jackson, P. K., & Greenberg, H. B. (2016). Comparative Proteomics Reveals Strain-Specific β-TrCP Degradation via Rotavirus NSP1 Hijacking a Host Cullin-3-Rbx1 Complex. PLoS pathogens, 12(10), [e1005929]. https://doi.org/10.1371/journal.ppat.1005929