1.G.14 The Influenza Virus Hemagglutinin/Fusion Pore-forming Protein (Influenza-H/FPP) Family
Hemagglutinin (HA) is the viral protein that facilitates the entry of influenza viruses into host cells. This protein controls two critical aspects of entry: virus binding and membrane fusion. In order for HA to carry out these functions, it must first undergo a priming step, proteolytic cleavage, which renders it fusion competent. Membrane fusion commences from inside the endosome after a drop in lumenal pH and an ensuing conformational change in HA that leads to the hemifusion of the outer membrane leaflets of the virus and endosome, the formation of a stalk between them, followed by pore formation (Hamilton et al. 2012). Influenza HA-catalyzed topological conversion of target membranes during fusion is associated with a loss of membrane integrity (Haldar et al. 2018). Staring et al. 2018 described the different mechanisms that viruses have evolved to escape the endosomal compartment and counteract cellular protection mechanisms.
Viral glycoproteins, such as influenza hemagglutinin (HA) and human immunodeficiency virus gp41, are anchored by a single TMS to the viral envelope membrane. The fusion peptides (FP) of the glycoproteins insert into the host membrane and initiate membrane fusion. The FP-TMS pair increases the lipid order at all positions, which has a greater lipid ordering effect than the each of the FP or TMD alone, and this effect reaches deeper into the membranes. This interaction may provide driving force in different stages of membrane fusion: initialization, transition from hemifusion stalk to transmembrane contact, and fusion pore formation (Lai and Freed 2015).
Influenza C virus hemagglutinin-fusion pore-forming protein of 655 aas and 4 TMSS, one N-terminal and three C-terminal but separated by about 100 residues. Pore formation is blocked by human interferon-induced transmembrane proteins such as IFM3 (Q01628) (Desai et al. 2014). The only spike of influenza C virus, the hemagglutinin-esterase-fusion glycoprotein (HEF) combines receptor binding, receptor hydrolysis and membrane fusion activities in a single protein. Like other hemagglutinating glycoproteins of influenza viruses, HEF is S-acylated, but only with stearic acid at a single cysteine located at the cytosol-facing end of the transmembrane region. S-acylation is essential for replication of influenza viruses A, B and C by affecting budding and/or membrane fusion (Wang et al. 2016).
Hemagglutinin-esterase-fusion glycoprotein of Influenza Virus
Hemagglutinin-esterase protein of 423 aas and 2 TM
Heagglutinin-esterase of Equine coronavirus
Fusion protein of 594 aas and 2 TMSs, N- and C-terminal.
Fusion protein of Wenling hoplichthys paramyxovirus