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

ABSTRACT: Inhibitor of Apoptosis Proteins act as E3 ubiquitin ligases to regulate NF-?B 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.

SUBMITTER: Gradzka S

PROVIDER: S-EPMC5943300 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Gradzka Sylwia S Thomas Oliver S OS Kretz Oliver O Haimovici Aladin A Vasilikos Lazaros L Wong Wendy Wei-Lynn WW Häcker Georg G Gentle Ian E IE

Cell death & disease 20180501 5

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. ...[more]

PMID: 29743550

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Project description:Glioblastoma multiforme (GBM) is the most common brain malignancy insensitive to radiotherapy (RT). Although macroautophagy/autophagy was reported to be a fundamental factor prolonging the survival of tumors under radiotherapeutic stress, the autophagic biomarkers coordinated to radioresistance of GBM are still lacking in clinical practice. Here we established radioresistant GBM cells and identified their protein profiles using tandem mass tag (TMT) quantitative proteomic analysis. It was found that SDC1 and TGM2 proteins were overexpressed in radioresistant GBM cells and tissues and they contributed to the poor prognosis of RT. Knocking down SDC1 and TGM2 inhibited the fusion of autophagosomes with lysosomes and thus enhanced the radiosensitivity of GBM cells. After irradiation, TGM2 bound with SDC1 and transported it from the cell membrane to lysosomes, and then bound to LC3 through its two LC3-interacting regions (LIRs), coordinating the encounter between autophagosomes and lysosomes, which should be a prerequisite for lysosomal EPG5 to recognize LC3 and subsequently stabilize the STX17-SNAP29-VAMP8 QabcR SNARE complex assembly. Moreover, when combined with RT, cystamine dihydrochloride (a TGM2 inhibitor) extended the lifespan of GBM-bearing mice. Overall, our findings demonstrated the EPG5 tethering mode with SDC1 and TGM2 during the fusion of autophagosomes with lysosomes, providing new insights into the molecular mechanism and therapeutic target underlying radioresistant GBM.Abbreviations: BafA1: bafilomycin A1; CQ: chloroquine; Cys-D: cystamine dihydrochloride; EPG5: ectopic P-granules 5 autophagy tethering factor; GBM: glioblastoma multiforme; GFP: green fluorescent protein; LAMP2: lysosomal associated membrane protein 2; LIRs: LC3-interacting regions; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NC: negative control; RFP: red fluorescent protein; RT: radiotherapy; SDC1: syndecan 1; SNAP29: synaptosome associated protein 29; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TGM2: transglutaminase 2; TMT: tandem mass tag; VAMP8: vesicle associated membrane protein 8; WT: wild type.

Dataset Information

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

Publications

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

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