Influenza A virus uncoating

Influenza A virus (IAV) is an enveloped virus of the Orthomyxoviridae with a negative-sense single-stranded RNA genome. During virus cell entry, viral and cellular cues are delivered in a stepwise manner within two distinct cellular compartments-the endosomes and the cytosol. Endosome maturation primes the viral core for uncoating by cytosolic host proteins and host-mediated virus disaggregation is essential for genome import and replication in the nucleus. Recent evidence shows that two well-known cellular proteins-histone deacetylase 6 (HDAC6) and karyopherin-β2 (kapβ2)-uncoat influenza virus. HDAC6 is 1 of 11 HDACs and an X-linked, cytosolic lysine deacetylase. Under normal cellular conditions HDAC6 is the tubulin deacetylase. Under proteasomal stress HDAC6 binds unanchored ubiquitin, dynein and myosin II to sequester misfolded protein aggregates for autophagy. Kapβ2 is a member of the importin β family that transports RNA-binding proteins into the nucleus by binding to disordered nuclear localization signals (NLSs) known as PY-NLS. Kapβ2 is emerging as a universal uncoating factor for IAV and human immunodeficiency virus type 1 (HIV-1). Kapβ2 can also reverse liquid-liquid phase separation (LLPS) of RNA-binding proteins by promoting their disaggregation. Thus, it is becoming evident that key players in the management of cellular condensates and membraneless organelles are potent virus uncoating factors. This emerging concept reveals implications in viral pathogenesis, as well as, the promise for cell-targeted therapeutic strategies to block universal virus uncoating pathways hijacked by enveloped RNA viruses.