@article{72a0f3057a99459c8a09e981fba1e08f,
title = "TRIM7 inhibits enterovirus replication and promotes emergence of a viral variant with increased pathogenicity",
abstract = "To control viral infection, vertebrates rely on both inducible interferon responses and less well-characterized cell-intrinsic responses composed of “at the ready” antiviral effector proteins. Here, we show that E3 ubiquitin ligase TRIM7 is a cell-intrinsic antiviral effector that restricts multiple human enteroviruses by targeting viral 2BC, a membrane remodeling protein, for ubiquitination and proteasome-dependent degradation. Selective pressure exerted by TRIM7 results in emergence of a TRIM7-resistant coxsackievirus with a single point mutation in the viral 2C ATPase/helicase. In cultured cells, the mutation helps the virus evade TRIM7 but impairs optimal viral replication, and this correlates with a hyperactive and structurally plastic 2C ATPase. Unexpectedly, the TRIM7-resistant virus has a replication advantage in mice and causes lethal pancreatitis. These findings reveal a unique mechanism for targeting enterovirus replication and provide molecular insight into the benefits and trade-offs of viral evolution imposed by a host restriction factor.",
keywords = "Antiviral immunity, E3 ubiquitin ligase, Enterovirus, Restriction factor, Viral evolution, Viral pathogenesis",
author = "Wenchun Fan and Mar, {Katrina B.} and Levent Sari and Gaszek, {Ilona K.} and Qiang Cheng and Evers, {Bret M.} and Shelton, {John M.} and Mary Wight-Carter and Siegwart, {Daniel J.} and Lin, {Milo M.} and Schoggins, {John W.}",
note = "Funding Information: We kindly thank many colleagues who provided key reagents, as noted in STAR Methods . We thank Andi Krumbholz, Marco Groth, and Roland Zell for their assistance in confirming single-nucleotide changes in human echovirus 18 isolates. We thank Julie Pfeiffer and Maikke Ohlson for thoughtful discussion and critical reading of the manuscript. Graphical abstract and select illustrations in the figures were created at Biorender.com . This study was supported in part by grants to J.W.S. ( NIH AI117922 and AI158124 , UT Southwestern Endowed Scholars Program , the Rita Allen Foundation , and an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund ). M.L. was supported by the Welch Foundation (grant I-1958-20180324 ). Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of funding agencies. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "24",
doi = "10.1016/j.cell.2021.04.047",
language = "English (US)",
volume = "184",
pages = "3410--3425.e17",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "13",
}