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

Wenchun Fan, Katrina B. Mar, Levent Sari, Ilona K. Gaszek, Qiang Cheng, Bret M. Evers, John M. Shelton, Mary Wight-Carter, Daniel J. Siegwart, Milo M. Lin, John W. Schoggins

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3410-3425.e17
Issue number13
StatePublished - Jun 24 2021


  • Antiviral immunity
  • E3 ubiquitin ligase
  • Enterovirus
  • Restriction factor
  • Viral evolution
  • Viral pathogenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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