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 inhibits 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.
Competing Interest Statement
MBF received funding from National Institute of Allergy and Infectious Diseases (NIAID), Biomedical Advanced Research and Development Authority (BARDA), Defense Advanced Research Projects Agency (DARPA), Gates Foundation, Aikido Pharma, Emergent, Astrazeneca, Novavax, Regeneron, and the CDC, which is outside the submitted work.
Footnotes
Changes have been made in response to reviews at eLife. Significantly, Fig S1D was added to show SIRT-1 knockdown efficiency, and former Fig S7 is now Fig 6. Verbiage and explanations of data and methods have also been changed throughout the text.
