Biology Reference
In-Depth Information
transmembrane proteins, namely hemagglutinin (HA), neuraminidase
(NA), and M2 proteins; and a peripheral membrane protein, namely
matrix (M1) protein (Fig. 2). HA and NA can be seen by electron
microscopy as protruding spikes of the virus envelope. Influenza virus
attaches to cells as a result of binding by HA to sialic-acid-containing
receptors and enters into cells by receptor-mediated endocytosis. In
the acidic environment of endosomes, HA undergoes conformational
changes that trigger fusion between virus envelopes and endosomal
membranes. Conversely, NA facilitates virus release from cells by
removing sialic acids from cells and progeny viruses.
13
HA and NA
have been shown to associate intrinsically with rafts, and residues
within the transmembrane (TM) domains of these proteins are impor-
tant for their raft-association.
14-17
Mutations at the exoplasmic half of
the HA and NA TM domains severely impaired raft association.
14-18
Cytoplasmic tails (CTs) of these proteins also contribute to their raft-
association.
19
In addition, HA requires three palmitoylated cystein
residues to associate with rafts.
19,20
Of these three cysteins, one is in
the TM domain and the others are in the CT. All three are highly con-
served among 15 HA subtypes.
21
Influenza virus glycoproteins are
therefore thought to have evolved to associate with rafts. Why do
influenza virus glycoproteins need to associate with rafts? It has been
shown that in polarized cells influenza virus buds exclusively from api-
cal cell membranes,
22
and analyses of lipid composition of purified
virions have suggested that influenza virus assembles at and buds from
rafts.
19,23
Both HA and NA are transported to the apical cell surface
when expressed alone,
24,25
and cholesterol was needed for HA apical
transport.
26
TM domains of both HA and NA were shown to contain
apical sorting signals.
18,27
In light of this, an attractive speculation was
that influenza virus uses rafts as a carrier to target its glycoproteins to
the apical cell surface, where virus particles assemble and bud. In sup-
port of this idea, some mutations that abolished the raft-association of
HA or NA retargeted these glycoproteins to the basolateral membrane
surface.
14-16,18
However, other mutagenesis results indicate that raft-
association does not necessarily correlate with the apical transport of HA
and NA.
14,15,19,27
A mutant HA that almost completely lost the ability
to associate with rafts was still transported to the apical cell surface.
17
