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

Cadwell, Ken; Debnath, Jayanta

(RIG-I) antiviral signaling. The presence of nucleic acid in the cytoplasm derived from intracellular pathogens induces transcription of IFN-I. The magnitude of this response is regulated by ATGs through both autophagy-dependent and -independent mechanisms. RIG-I binds short double-stranded RNA with a 5′ppp moiety, which exposes the caspase activation and recruitment domain (CARD) to allow interaction with the CARD of mitochondrial antiviral signaling protein (MAVS; Yoneyama et al., 2004; Kawai et al., 2005; Meylan et al., 2005; Seth et al., 2005) . After this CARD-CARD interaction, MAVS oligomerizes on the mitochondrial outer surface to activate TBK-1, which in turn leads to the phosphorylation and nuclear translocation of the transcription factors IFN regulatory factor 3 (IRF3), IRF7, and NFκb (Honda et al., 2005; Seth et al., 2005) . The ATG5-ATG12 conjugate inhibits this RNA recognition pathway by binding the CARDs of RIG-I and MAVS (Fig. 3 ; Jounai et al., 2007) . Although it is unclear how these interactions prevent MAVS function, the direct binding of ATG5-ATG12 to CARDs suggests that the mechanism is autophagy-independent. An alternative mechanism involves increased IFN-I production upon disruption of mitophagy. ROS from damaged mitochondria accumulate upon ATG5 deletion, which enhances RIG-I signaling ( Fig. 3 ; Tal et al., 2009) . Mitophagy also mediates the concurrent degradation of MAVS upon its translocation to mitochondria. The recruitment of the ATG16L1-ATG5-ATG12 complex to mitochondria by NLRX1 and elongation factor Tu (TUFM) decreases MAVS activity ( Fig. 3 ; Lei et al., 2012) . The importance of this pathway is highlighted by the observation that the human parainfluenza virus type 3 matrix protein induces mitophagy through interaction with TUFM, leading to decreased immune signaling and increased viral replication (Ding et al., 2017) . Also, a single base substitution that confers the ability of the viral polymerase basic protein 2 to bind TUFM and induce autophagy allows avian influenza virus to infect human cells (Kuo et al., 2017) . Most likely through a similar process, the mitochondrial protein COX5B binds ATG5 and MAVS, and reduces ROS and IFN-I production during viral infection (Zhao et al., 2012) . The commonality in these studies is that inhibiting the ATG5-ATG12 conjugate increases IFN-I and decreases replication of RNA viruses. . ATGs in inflammatory and immune signaling. ATGs regulate immune signaling cascades through autophagy-dependent and -independent mechanisms. The mitochondrial protein TUFM recruits the ATG16L1-ATG5-ATG12 complex to mediate the autophagic removal of mitochondria that produce ROS, an activator of RIG-I signaling and the NLRP3 inflammasome. By targeting mitochondria, autophagy further inhibits IFN-I production by removing the signaling intermediate MAVS, which aggregates on mitochondrial surfaces downstream of viral RNA recognition by RIG-I. Also, the ATG5-ATG12 complex inhibits RIG-I and MAVS through an inhibitory binding event. Beclin-1 prevents sustained signaling by inducing the autophagic removal of cytosolic DNA and inhibiting cGAS through direct binding. cGAMP generated by cGAS activates ULK1 to inhibit STI NG in a negative feedback loop. ATG9L1 interferes with the trafficking of STI NG to prevent continuous TBK-1 activation. 2013). Similar to RNA sensing by RIG-I, STI NG (Stimulator of interferon genes) mediates a TBK-1 dependent signaling cascade in the presence of cGAMP (Chen