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).