Home LiteratureArticle Details
PMID: 29743550 Published · epublish English Journal Article

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

Cell death & disease ·Vol. 9 ·No. 5 ·2018-00-01 ·Pages 529

Gradzka S, Thomas OS, Kretz O, Haimovici A, Vasilikos L, Wong WW, Häcker G, Gentle IE

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.

MeSH Terms
Animals Autophagosomes Baculoviral IAP Repeat-Containing 3 Protein/genetics,metabolism Crohn Disease/genetics,metabolism,pathology Inhibitor of Apoptosis Proteins/genetics,metabolism Lysosomes/genetics,metabolism Membrane Fusion Mice Mitophagy
Chemicals
Birc4 protein, mouse Inhibitor of Apoptosis Proteins Baculoviral IAP Repeat-Containing 3 Protein
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Gradzka Sylwia
Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany. | Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Thomas Oliver S
Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany. | Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Kretz Oliver
Renal Division, University Medical Center Freiburg, Freiburg, Germany. | Department of Neuroanatomy, University Freiburg, Freiburg, Germany. | Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Haimovici Aladin
Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany. | Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Vasilikos Lazaros
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Wong Wendy Wei-Lynn
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Häcker Georg
Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany. | Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Gentle Ian E ORCID
Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany. ian.gentle@uniklinik-freiburg.de. | Faculty of Medicine, University of Freiburg, Freiburg, Germany. ian.gentle@uniklinik-freiburg.de.
References (42)
42 references, click to expand
  1. Control of RAB7 activity and localization through the retromer-TBC1D5 complex enables RAB7-dependent mitophagy.
    EMBO J. 2018 Jan 17;37(2):235-254 PMID: 29158324
  2. XIAP variants in male Crohn's disease.
    Gut. 2015 Jan;64(1):66-76 PMID: 24572142
  3. Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK.
    Nat Immunol. 2008 Dec;9(12):1371-8 PMID: 18997794
  4. X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis.
    Clin Immunol. 2013 Oct;149(1):133-41 PMID: 23973892
  5. IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.
    Cell. 2007 Nov 16;131(4):682-93 PMID: 18022363
  6. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling.
    Nat Immunol. 2008 Dec;9(12):1364-70 PMID: 18997792
  7. Using enhanced-mitophagy to measure autophagic flux.
    Methods. 2015 Mar;75:105-11 PMID: 25498004
  8. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease.
    Gut. 2017 Jun;66(6):1060-1073 PMID: 26953272
  9. Autophagy: machinery and regulation.
    Microb Cell. 2016 Dec 01;3(12 ):588-596 PMID: 28357331
  10. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1.
    Nat Genet. 2007 Feb;39(2):207-11 PMID: 17200669
  11. Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole.
    J Biol Chem. 2006 Apr 21;281(16):11374-83 PMID: 16495224
  12. The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin 17.
    Mol Biol Cell. 2014 Apr;25(8):1327-37 PMID: 24554770
  13. Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling.
    EMBO Mol Med. 2013 Aug;5(8):1278-95 PMID: 23818254
  14. Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest.
    Mol Cell. 2011 Jun 24;42(6):731-43 PMID: 21700220
  15. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.
    Nature. 2001 May 31;411(6837):603-6 PMID: 11385577
  16. Induction of genuine autophagy by cationic lipids in mammalian cells.
    Autophagy. 2010 May;6(4):449-54 PMID: 20383065
  17. Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond.
    Semin Immunopathol. 2015 Jul;37(4):335-47 PMID: 25994946
  18. Proapoptotic signalling through Toll-like receptor-3 involves TRIF-dependent activation of caspase-8 and is under the control of inhibitor of apoptosis proteins in melanoma cells.
    Cell Death Differ. 2010 Jun;17(6):942-51 PMID: 20019748
  19. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers.
    J Allergy Clin Immunol. 2014 Nov;134(5):1131-41.e9 PMID: 24942515
  20. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.
    Nature. 2006 Nov 2;444(7115):110-4 PMID: 17080092
  21. Digesting the Expanding Mechanisms of Autophagy.
    Trends Cell Biol. 2016 Aug;26(8):624-35 PMID: 27050762
  22. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation.
    Immunity. 2012 Feb 24;36(2):215-27 PMID: 22365665
  23. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations.
    Lancet. 2001 Jun 16;357(9272):1925-8 PMID: 11425413
  24. cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner.
    Blood. 2014 Apr 17;123(16):2562-72 PMID: 24497535
  25. Immunologic manifestations of autophagy.
    J Clin Invest. 2015 Jan;125(1):75-84 PMID: 25654553
  26. Autophagy and autophagy-related proteins in the immune system.
    Nat Immunol. 2015 Oct;16(10):1014-24 PMID: 26382870
  27. Versatile roles of k63-linked ubiquitin chains in trafficking.
    Cells. 2014 Nov 12;3(4):1027-88 PMID: 25396681
  28. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.
    Nature. 2001 May 31;411(6837):599-603 PMID: 11385576
  29. NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria.
    Cell. 2016 Feb 25;164(5):896-910 PMID: 26919428
  30. Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response.
    Cell Microbiol. 2012 Jun;14 (6):791-807 PMID: 22309232
  31. At the end of the autophagic road: an emerging understanding of lysosomal functions in autophagy.
    Trends Biochem Sci. 2014 Feb;39(2):61-71 PMID: 24369758
  32. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.
    J Cell Biol. 2008 Dec 1;183(5):795-803 PMID: 19029340
  33. ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn's disease pathogenesis.
    Gastroenterology. 2010 Nov;139(5):1630-41, 1641.e1-2 PMID: 20637199
  34. XIAP deficiency is a mendelian cause of late-onset IBD.
    Gut. 2014 Jun;63(6):1031-2 PMID: 24326742
  35. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry.
    Nat Immunol. 2010 Jan;11(1):55-62 PMID: 19898471
  36. XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation.
    Cell Rep. 2014 Jun 26;7(6):1796-808 PMID: 24882010
  37. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity.
    Mol Cell. 2012 Jun 29;46(6):746-58 PMID: 22607974
  38. TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNFalpha.
    J Cell Biol. 2008 Jul 14;182(1):171-84 PMID: 18606850
  39. Cleaning House: Selective Autophagy of Organelles.
    Dev Cell. 2017 Apr 10;41(1):10-22 PMID: 28399394
  40. Neuroinflammatory paradigms in lysosomal storage diseases.
    Front Neurosci. 2015 Oct 30;9:417 PMID: 26578874
  41. Development of a novel method for quantification of autophagic protein degradation by AHA labeling.
    Autophagy. 2014 May;10(5):901-12 PMID: 24675368
  42. Smac mimetics: implications for enhancement of targeted therapies in leukemia.
    Leukemia. 2010 Dec;24(12 ):2100-9 PMID: 20844561
Article Info
Journal
Cell death & disease
Abbr.
Cell Death Dis
ISSN
2041-4889
DOI
10.1038/s41419-018-0508-y
Email
ian.gentle@uniklinik-freiburg.de
Published
2018-00-01
Epub
2018-00-01
Pages
529
Language
English
Region
England
NLM ID
101524092
PMCID
PMC5943300
Subset
IM
External Links
PubMed source DOI: 10.1038/s41419-018-0508-y PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2