SIRT-1 is required for release of enveloped enteroviruses

Abstract

Enterovirus D68 is a re-emerging enterovirus that causes acute respiratory illness in infants and has recently been linked to Acute Flaccid Myelitis. Here, we show that the histone deacetylase, SIRT-1, is essential for autophagy and EV-D68 infection. Knockdown of SIRT-1 blocks autophagy and reduces EV-D68 extracellular titers. The proviral activity of SIRT-1 does not require its deacetylase activity or functional autophagy. SIRT-1’s proviral activity is, we demonstrate, mediated through the repression of ER stress. Inducing ER stress through thapsigargin treatment or SERCA2A knockdown in SIRT-1 knockdown cells had no additional effect on EV-D68 extracellular titers. Knockdown of SIRT-1 also decreases poliovirus and SARS-CoV-2 titers but not coxsackievirus B3. In non-lytic conditions, EV-D68 is primarily released in an enveloped form, and SIRT-1 is required for this process. Our data show that SIRT-1, through its translocation to the cytosol, is critical to promote the release of enveloped EV-D68 viral particles.

Transcription factor EB (TFEB) interaction with RagC is disrupted during Enterovirus D68 Infection

“…This finding is different from the CVB3 paper cited above, which shows TFEB translocation to the nucleus late during infection, indicating that CVB3 and EV-D68 may use TFEB somewhat differently. The disparity between EV-D68 and CVB3 regarding TFEB localization during infection is unsurprising since we have recently shown that the deacetylase SIRT-1, which deacetylates TFEB, is essential for EV-D68 release but not for CVB3 release (20). These findings suggest that EV-D68 and CVB3 can engage the same cellular process differently.…”