Taking a detour from all things interferon to present work on a non-interferon based restriction factor. Postdoc @Wenchun_Fan discovered TRIM7 as a potent inhibitor of multiple human enteroviruses. Now out in @CellPressNews @UTSWNews
authors.elsevier.com/a/1d9saL7PXe%7…
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authors.elsevier.com/a/1d9saL7PXe%7…
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Through virologic, biochemical, and cell biological approaches, Wenchun found that TRIM7 functions as an E3 ligase that targets enterovirus 2BC for ubiquitination and proteasome-dependent degradation. This wipes out viral replication. 2/7 
He then isolated in cell culture a coxsackievirus B3 variant that is resistant to TRIM7 effects. The variant virus contains a single point mutation T323A in viral 2C. This allows 2BC to evade TRIM7 binding. But it also results in an altered 2C protein. 3/7
Our colleagues in Milo Lin's lab at UTSW performed molecular dynamics simulations and found that the mutant 2C protein is hyperplastic. The T323A mutation occurs near a natural fulcrum that gives the variant 2C increased "breathing" motion. 4/7
In addition to breathing, there's an also an increase in "twisting" motion. This hyperplasticity results in augmented 2C ATPase activity, and in cell culture, this naturally attenuates the virus to some degree. 5/7
However, in vivo, the variant virus (red) is far more pathogenic than the parental virus. It replicates to higher titers in all tissues examined and causes a severe pancreatitis. (thx to @katrinabmar for in vivo collab) 6/7
As a therapeutic proof of concept, we teamed up with @DJSiegwart lab and showed that lipid nanoparticles loaded with TRIM7 mRNA were able to suppress viral replication in cells (left) and in vivo (right). Congrats @Wenchun_Fan & all collabs for this tour de force effort. 7/7
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