Host-cell pathways regulating influenza hemagglutinin post-translational maturation

Host-cell pathways regulating influenza hemagglutinin (HA) post-translational maturation encompass a series of essential biochemical processes that transform the nascent HA polypeptide into a functional, infectious protein. This maturation occurs within the host's secretory pathway and includes N-linked glycosylation, chaperone-mediated folding (involving calnexin and calreticulin), disulfide bond formation, and trimerization in the endoplasmic reticulum (ER) (Sun & Whittaker, 2013, DOI: 10.1111/j.1600-0854.2012.01456.x). A critical final step is the proteolytic cleavage of the precursor HA0 into HA1 and HA2 subunits by host-cell proteases such as Furin or members of the Type II Transmembrane Serine Protease (TTSP) family, like TMPRSS2 and TMPRSS4, which is a prerequisite for viral membrane fusion and infectivity (Böttcher-Friebertshäuser et al., 2013, DOI: 10.1016/j.virs.2012.11.001). Additionally, palmitoylation of the HA cytoplasmic tail by host ZDHHC enzymes is often required for efficient viral assembly. Targeting these host pathways, rather than the virus itself, represents a host-directed therapeutic strategy aimed at reducing the likelihood of viral resistance. For example, ER glucosidase inhibitors like celgosivir disrupt HA folding, while protease inhibitors like camostat mesylate block the activation of the virus, effectively neutralizing its ability to spread (Warfield et al., 2016, DOI: 10.1371/journal.pone.0150640).

Other names

Influenza HA maturation pathwaysHost-directed influenza targetsHA0 processing machineryInfluenza hemagglutinin post-translational modification

Inhibition of host-cell proteases (e.g., TMPRSS2, Furin) to prevent HA0 cleavage; inhibition of ER glucosidases to disrupt HA folding and trafficking; inhibition of palmitoyltransferases to prevent HA membrane anchoring.