VSIG4
A second cell-surface complement receptor implicated in autophagy
induction is V-set and immunoglobulin domain containing 4 (VSIG4), also
known as Complement Receptor of the Immunoglobulin superfamily (CRIg),
which binds to both C3b and iC3b (Helmy et al., 2006). VSIG4 is
expressed on macrophages and contributes to complement-dependent
clearance of circulating particles by liver Kupffer cells. VSIG4 also
contributes to phagocytosis and subsequent phagosome acidification,
leading to enhanced killing of complement-opsonised bacteria (Kim et
al., 2013). In addition to this, a role for VSIG4 has also been shown in
the killing of intracellular bacteria via autophagy induction.
Listeria monocytogenes is an intracellular pathogen that is able
to escape from phagosomes into the cytosol, therefore avoiding killing.
Kim et al found that once Listeria had escaped into the
cytosol, cross-linking of cell-surface VSIG4 by specific antibodies led
to formation of LC3-II-positive autophagosomes, which contained labeled
bacteria (Kim et al., 2016). As a result, fewer viable bacteria were
isolated from cell lysates. In comparison, induction of autophagy in
infected cells by serum starvation did not result in decreases in
bacterial numbers compared to control cells, showing that
VSIG4-triggered autophagy increased targeted capture and killing of
intracellular bacteria via xenophagy. This was attributed to the
increased polyubiquitinylation of intracellular bacteria found after
VSIG4 stimulation, which recruits autophagy ubiquitin-binding receptor
proteins such as P6214. Although VSIG4 signaling is
not fully understood, the adaptor protein MyD88 was implicated, which
phosphorylates and activates Beclin 1 (Shi & Kehrl, 2008), therefore
triggering autophagosome formation. Overexpression of VSIG4 in HeLa
cells also conferred the same function, allowing them to kill
intracellular bacteria by xenophagy, while conversely, macrophages from
VSIG4-/- mice supported greater intracellularListeria growth in the presence of VSIG4 receptor stimulation,
compared to WT macrophages. While these results clearly show the ability
of VSIG4 to trigger autophagy and targeted xenophagy, the use of
cross-linking antibodies is not physiological. While
complement-opsonised Listeria triggered autophagy in macrophages
more efficiently than unopsonised bacteria, once bacteria have entered
the intracellular environment, one would not expect continued surface
VSIG4 signaling. However, it is likely that during an ongoing infection,
the presence of extracellular bacteria or DAMPs would provide complement
activation and VSIG4 stimulation, resulting in increased autophagy to
clear potential intracellular pathogens.