Inhibitor of apoptosis proteins are required for effective fusion of autophagosomes with lysosomes

Inhibitor of Apoptosis Proteins act as E3 ubiquitin ligases to regulate NF kB signalling from multiple pattern recognition receptors including NOD2, as well as TNF Receptor Superfamily members Foss of XIAP in humans causes X linked Lymphoproliferative disease type 2 (XlP 2) and is often associated with Crohn's disease Crohn's disease is also caused by mutations in the gene encoding NOD2 but the mechanisms behind Crohn's disease development in XIAP and NOD2 deficient patients are still unknown Numerous other mutations causing Crohn's Disease occur in genes controlling various aspects of autophagy, suggesting a strong involvement of autophagy in preventing Crohn's disease Here we show that the IAP proteins clAP2 and XIAP are required for efficient fusion of lysosomes with autophagosomes IAP inhibition or loss of both clAP2 and XIAP resulted in a strong blockage in autophagic flux and mitophagy, suggesting that XIAP deficiency may also drive Crohn's Disease due to defects in autophagy.