Journal
ELIFE
Volume 7, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.39494
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Funding
- Thrasher Research Fund
- National Institute of Allergy and Infectious Diseases [K99 AI135031, R01 AI125249, U19 AI116484]
- Walter V. and Idun Berry Foundation
- Institute for Immunity, Transplantation and Infection, Stanford University Young Investigator Award
- National Natural Science Foundation of China [81788104, 31770990]
- Chinese Academy of Sciences Strategic Priority Research Program [XDPB03]
- Howard Hughes Medical Institute
- U.S. Department of Veterans Affairs [GRH0022]
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Rotaviruses (RVs), a leading cause of severe diarrhea in young children and many mammalian species, have evolved multiple strategies to counteract the host innate immunity, specifically interferon (IFN) signaling through RV non-structural protein 1 (NSP1). However, whether RV structural components also subvert antiviral response remains under-studied. Here, we found that MAVS, critical for the host RNA sensing pathway upstream of IFN induction, is degraded by the RV RNA methyl- and guanylyl-transferase (VP3) in a host-range-restricted manner. Mechanistically, VP3 localizes to the mitochondria and mediates the phosphorylation of a previously unidentified SPLTSS motif within the MAVS proline-rich region, leading to its proteasomal degradation and blockade of IFN-lambda production in RV-infected intestinal epithelial cells. Importantly, VP3 inhibition of MAVS activity contributes to enhanced RV replication and to viral pathogenesis in vivo. Collectively, our findings establish RV VP3 as a viral antagonist of MAVS function in mammals and uncover a novel pathogen-mediated inhibitory mechanism of MAVS signaling.
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