4.8 Article

TRIM7 inhibits enterovirus replication and promotes emergence of a viral variant with increased pathogenicity

期刊

CELL
卷 184, 期 13, 页码 3410-+

出版社

CELL PRESS
DOI: 10.1016/j.cell.2021.04.047

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资金

  1. NIH [AI117922, AI158124]
  2. UT Southwestern Endowed Scholars Program
  3. Rita Allen Foundation
  4. Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund
  5. Welch Foundation [I-1958-20180324]

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The research reveals that TRIM7 is a novel cell-intrinsic antiviral effector that restricts the spread of multiple human enteroviruses by targeting the viral 2BC protein for degradation. Selective pressure from TRIM7 led to the emergence of a TRIM7-resistant coxsackievirus with a mutation in the viral 2C ATPase/helicase.
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.

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