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

Cadwell, Ken; Debnath, Jayanta

Here, we use IBD, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) as examples of how ATGs contribute to complex inflammatory diseases. IBD includes Crohn's disease and ulcerative colitis, and is frequently a debilitating condition that involves chronic inflammation in the small intestine or colon, although any part of the gastrointestinal tract can be affected. Many genetic variants that increase risk of IBD, including several known to affect autophagy, are also found in individuals without disease (Lassen and Xavier, 2017) . A particularly common polymorphism in ATG16L1 (up to 50% heterozygosity in certain populations) linked to Crohn's disease introduces a caspase-3 cleavage site that destabilizes the protein product (ATG16L1 T300A ), thereby causing a reduction in autophagy (Lassen et al., 2014; Murthy et al., 2014) . ATG16L1 T300A is associated with structural defects in Paneth cells, intestinal epithelial cells that produce antimicrobial granules (Cadwell et al., 2008) . Additional inflammatory pathologies in the intestinal epithelium of Atg16L1 mutant mice is triggered by a commensal enteric virus (Cadwell et al., 2010; Kernbauer et al., 2014) , or by dual deletion of ATG16L1 and the ER stress transcription factor XBP-1 in Paneth cells (Adolph et al., 2013) . These findings are consistent with epidemiological observations suggesting that IBD is caused by the confluence of multiple genetic and environmental susceptibility factors.