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

Cadwell, Ken; Debnath, Jayanta

Several findings support the idea that the classic autophagy function of ATG16L1 is critical for protecting the epithelial barrier and preventing a sustained immune reaction. ATG-deficient Paneth cells display unresolved ER stress and mitochondrial damage that contribute to necroptosis, a type of programmed necrotic cell death (Diamanti et al., 2017; Matsuzawa-Ishimoto et al., 2017; Tschurtschenthaler et al., 2017) . These observations suggest that the organelle homeostasis function of autophagy is important to counteract the secretory burden of this highly differentiated cell type and prevent inflammatory sequelae. Also, ATGs are generally required to protect the epithelial barrier, potentially through xenophagy or mediating mucus production by goblet cells (Benjamin et al., 2013; Conway et al., 2013b; Patel et al., 2013) . An important role for autophagy in immune cells should also be considered. Increased inflammasome activity in macrophages and decreased differentiation of antiinflammatory T cells are both consequences of ATG16L1 inhibition, and can cause intestinal inflammation (Saitoh et al., 2008; Chu et al., 2016; Kabat et al., 2016) . However, many of these studies rely on animal models in which classic autophagy and related processes are difficult to distinguish. ATG16L1 T300A disrupts secretory autophagy, leading to impaired exocytosis of lysozyme from Paneth cells during Salmonella infection (Bel et al., 2017) , and the effect of ATG16L1 T300A on the necroptosis signaling complex likely involves disruption in ATG-mediating immune signaling (Matsuzawa-Ishimoto et al., 2017) . In addition to being an unstable protein, ATG16L1 T300A displays impaired binding with TMEM59, a transmembrane protein that mediates the trafficking of LC3 + vesicles through a process distinct from classic autophagy (Boada-Romero et al., 2016) . Also, with the exception of graft-versus-host disease (Hubbard-Lucey et al., 2014) , the IBD variant of ATG16L1 is not linked to other inflammatory disorders associated with autophagy dysfunction, such as Vici syndrome . Thus, investigating the potential nonautophagic functions of ATG16L1 in maintaining the intestinal barrier remains a critically important future direction.