ATG9A facilitates the biogenesis of influenza A virus liquid condensates near the ER by dissociating recycling vesicles from microtubules

Abstract

AbstractMany viruses that threaten public health establish condensates via phase transitions to complete their lifecycles, and knowledge on such processes is key for the design of new antivirals. In the case of influenza A virus, liquid condensates known as viral inclusions are sites dedicated to the assembly of its 8-partite RNA genome. Liquid viral inclusions emerge near the endoplasmic reticulum (ER) exit sites, but we lack the molecular understanding on how the ER contributes to their biogenesis. We show here that viral inclusions develop at remodeled ER sites and display dynamic interactions using the ER, including fusion and fission events and sliding movements. We also uncover a novel role for the host factor, ATG9A, in mediating the exchange of viral inclusions between the ER and microtubules. Depletion of ATG9A arrests viral inclusions at microtubules and prevents their accumulation at the ER, leading to a significantly reduced production of viral genome complexes and infectious virions. In light of our recent findings, we propose that a remodeled ER supports the dynamics of liquid IAV inclusions, with ATG9A acting locally to facilitate their formation. This work advances our current knowledge regarding influenza genome assembly, but also reveals new roles for ATG9A beyond its classical involvement in autophagy.