Figure 4.

IAV capsid uncoating, genome release and nuclear import. Endosome acidification occurs progressively from the cell periphery toward the microtubule-organizing center (MTOC). Late endosomal acidification (pH~6) triggers change of the homotrimeric glycoprotein HA mediating fusion between the viral envelope and the endosome membrane. Influx of protons and efflux of potassium from the virus core happen through the acid-activated viral ion channel M2. The pH drop triggers the activation of a histidine cluster in the virus capsid, contributed by three sequential M1 monomers, and promotes the capsid disassembly. Further the vRNPs dissociate from the M1 proteins. Free ubiquitin (Ub) chains derived from virus particles activate the aggresome processing pathway (APP) and recruit HDAC6 through its Ub-binding zinc finger domain (HDAC6 ZnF). Deubiquitinases (DUBs) could be involved in unanchored Ub formation. HDAC6 binds to M1 and to NP from vRNPs. HDAC6 by a region between its catalytic domains also binds motor proteins in microtubules and myosin II in actin microfilaments generating physical forces that help dissociate the M1 proteins, disassembling the virus capsid. The epidermal growth factor receptor pathway substrate 8 (EPS8) and transportin-1 (TNPO1) interact with M1 from the capsid and vRNPs, contributing to the disaggregation of the vRNP-associated M1 and vRNP debundling in the cytosol. In this way, vRNPs are transported by importin α/β to the nucleus as individual rod-shaped structures. PDB: TNPO1 (2Z5J), EPS8 (2E8M), importin α (4B18), DUB (6K9P).