Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins

Cadwell, Ken; Debnath, Jayanta

ATGs and inflammasome activation. Inflammasomes are multiprotein complexes that induce the cleavage of pro-IL-1β and pro-IL-18 by caspase-1 to generate the activate forms of these cytokines (Sharma and Kanneganti, 2016) . The NLRP3 inflammasome responds to a variety of stimuli that directly or indirectly cause the release of ROS and DNA from leaky mitochondria (e.g., bacterial toxins and microcrystalline substances). Inhibiting mitophagy, therefore, leads to accumulation of damaged mitochondria that induce pathological cytokine production downstream of NLRP3 inflammasome activation ( Fig. 3 ; Saitoh et al., 2008; Zhong et al., 2016) . ATGs also inhibit the caspase-11 inflammasome, which is activated by the bacterial cell wall component lipopolysaccharide in the cytosol. When IFN-inducible GTPases attack the Salmonellacontaining vacuole as part of the host defense mechanism, LC3 is recruited to the damaged membrane by the linker protein NDP52 to mediate the autophagic sequestration of bacteria and lipopolysaccharide, which inhibits inflammasome activation (Meunier et al., 2014) . Hence, it is likely that removal of damaged vesicles and organelles (or their contents) through classic autophagy restrains inflammasome activity, thereby explaining why inhibiting autophagy proteins such as ATG16L1 enhance IL-1β and IL-18 production.