Activation of autophagy by the membrane attack complex
The MAC forms a multimeric pore that breaches cell membranes, but while
this mechanism evolved to attack microorganisms, MAC can be deposited on
bystander host cells during infection and particularly in autoimmune or
autoinflammatory disease, causing haemolysis and cell death. For
example, MAC-induced cell death is a feature of complement-related
nephropathy (Ma, Sandor, & Beck, 2013). Sub-lytic levels of MAC were
found to trigger autophagy in podocytes in vitro, driving LC3-I/II
conversion, while pharmacological autophagy inhibition increased levels
of apoptosis, and enhancing autophagy with rapamycin decreased resulting
levels of cell death (Lv, Yang, Chen, & Zhang, 2016). Autophagy is
therefore a cytoprotective response to cellular stress provoked by MAC
disruption of membranes. These results were confirmed in a separate
study of podocytes from human patients with idiopathic membranous
nephropathy, which had increased MAC deposition, and accumulations of
LC3-positive puncta, increased levels of P62, and increased expression
of Beclin 1, but no increase in autolysosomes (Liu et al., 2017). This
suggests that autophagosome formation is induced by MAC, but that these
do not fuse with functional lysosomes, resulting in ’frustrated’
autophagy. The MAC was internalised and triggered permeabilisation of
lysosomal membranes, preventing their adequate acidification and
function, leading to accumulation of autophagosomes with undigested
contents.
MAC therefore triggers initiation of autophagy, but internalisation of
the C5b-9 membrane pore by endocytosis may lead to defective lysosomal
function, limiting the potential upregulation of fully functional
autophagy, although this may be augmented by application of
autophagy-stimulating drugs such as rapamycin. It is unlikely that
induction of autophagy by MAC is a specific response to complement, but
rather a general cellular response to breaching of the surface membrane,
as autophagy is also upregulated by multiple membrane pore-forming
toxins in both C. Elegans (Chen et al., 2017) and mammalian cells
(Kloft et al., 2010).