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

Sylwia Gradzka,Oliver Kretz,Aladin Haimovici,Wendy Wei-Lynn Wong,Ian E Gentle,Lazaros Vasilikos,Oliver S Thomas,Georg Häcker

doi:10.1038/s41419-018-0508-y

Abstract

Inhibitor of Apoptosis Proteins act as E3 ubiquitin ligases to regulate NF-κB signalling from multiple pattern recognition receptors including NOD2, as well as TNF Receptor Superfamily members. Loss 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 cIAP2 and XIAP are required for efficient fusion of lysosomes with autophagosomes. IAP inhibition or loss of both cIAP2 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.

Highlights

IAPs are ubiquitin ligases that regulate the activity of TNF Super Family Receptors (TNFSFR), TLRs and NOD receptors
XIAP depletion alone in humans leads to disease but XIAP−/− mice are in most aspects normal, they can be induced to develop disease similar to X-linked Lymphoproliferative disease type 2 (XLP-2) in humans by infection with a herpes virus, MHV-6838
One might expect that if there was an absolute requirement for XIAP or cIAP2 in autophagy that mice deficient for either alone would present with phenotypes associated with defects in Relatively little is known about the substrates of XIAP, ubiquitylation of RIPK2 at NOD2 receptors was shown to be required for NOD2 activation of NF-κB13

Summary

Introduction

IAPs are ubiquitin ligases that regulate the activity of TNF Super Family Receptors (TNFSFR), TLRs and NOD receptors. By attaching ubiquitin onto substrates such as RIPK1 they regulate the activation of NF-κB and determine the outcome of signals from these receptors. Their inhibition results in skewing of signals towards death and production of an inflammatory cytokine response[1,2,3,4]. The three best characterised and functionally related IAP members are cIAP1, cIAP2 and XIAP. Less is known about XIAP and its regulation other than it is required for NF-κB signals from

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