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Article: Supramolecular Complexes in Cell Death and Inflammation and Their Regulation by Autophagy.

Gentle, Ian E

Frontiers in cell and developmental biology

2019 Volume 7, Page(s) 73

Abstract: Signaling activation is a tightly regulated process involving myriad posttranslational modifications such as phosphorylation/dephosphorylation, ubiquitylation/deubiquitylation, proteolytical cleavage events as well as translocation of proteins to new ... ...

Abstract	Signaling activation is a tightly regulated process involving myriad posttranslational modifications such as phosphorylation/dephosphorylation, ubiquitylation/deubiquitylation, proteolytical cleavage events as well as translocation of proteins to new compartments within the cell. In addition to each of these events potentially regulating individual proteins, the assembly of very large supramolecular complexes has emerged as a common theme in signal transduction and is now known to regulate many signaling events. This is particularly evident in pathways regulating both inflammation and cell death/survival. Regulation of the assembly and silencing of these complexes plays important roles in immune signaling and inflammation and the fate of cells to either die or survive. Here we will give a summary of some of the better studied supramolecular complexes involved in inflammation and cell death, particularly with a focus on diseases caused by their autoactivation and the role autophagy either plays or may be playing in their regulation.
Language	English
Publishing date	2019-05-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2019.00073
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Article ; Online: Pattern Recognition Receptors of Nucleic Acids Can Cause Sublethal Activation of the Mitochondrial Apoptosis Pathway during Viral Infection.

Gradzka-Boberda, Sylwia / Gentle, Ian E / Häcker, Georg

Journal of virology

2022 Volume 96, Issue 18, Page(s) e0121222

Abstract: The mitochondrial apoptosis pathway has the function to kill the cell, but recent work shows that this pathway can also be activated to a sublethal level, where signal transduction can be observed but the cell survives. Intriguingly, this signaling has ... ...

Abstract	The mitochondrial apoptosis pathway has the function to kill the cell, but recent work shows that this pathway can also be activated to a sublethal level, where signal transduction can be observed but the cell survives. Intriguingly, this signaling has been shown to contribute to inflammatory activity of epithelial cells upon infection with numerous agents. This suggests that microbial recognition can generate sublethal activity in the mitochondrial apoptosis pathway. Because this recognition is achieved by pattern recognition receptors (PRRs), it also implies that PRR signals are linked to the mitochondrial apoptosis apparatus. We here test this hypothesis during infection of epithelial cells with modified vaccinia virus Ankara (MVA). MVA recognition is achieved through receptors specific for nucleic acids, and we present evidence that the three receptors, Toll-like receptor 3 (TLR3), RIG-I/MDA5, and cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING), are involved in this signaling. When stimulated directly by specific ligands, all three receptors could trigger sublethal apoptosis signals. During infection with MVA, sublethal apoptosis signals were unmasked in X-linked IAP (XIAP)-deficient cells, where apoptosis induction was observed. Deletion of any of the three signaling adapters, TRIF, MAVS, and STING, reduced the DNA damage response, a sensitive measure of sublethal apoptosis signals. Our results suggest that PRRs signal via mitochondria, where they generate sublethal signals through the BCL-2-family, which may contribute to the response to infectious agents.
MeSH term(s)	Adaptor Proteins, Vesicular Transport/immunology ; Apoptosis ; Humans ; Immunity, Innate ; Mitochondria/immunology ; Nucleic Acids ; Nucleotidyltransferases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Receptors, Pattern Recognition/immunology ; Toll-Like Receptor 3/metabolism ; Vaccinia virus ; Virus Diseases/immunology
Chemical Substances	Adaptor Proteins, Vesicular Transport ; Nucleic Acids ; Proto-Oncogene Proteins c-bcl-2 ; Receptors, Pattern Recognition ; Toll-Like Receptor 3 ; Nucleotidyltransferases (EC 2.7.7.-)
Language	English
Publishing date	2022-09-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.01212-22
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Article ; Online: GM-CSF suppresses antioxidant signaling and drives IL-1β secretion through NRF2 downregulation.

Di Carlo, Sara / Häcker, Georg / Gentle, Ian E

EMBO reports

2022 Volume 23, Issue 8, Page(s) e54226

Abstract: GM-CSF is a potent inflammatory cytokine regulating myeloid cell differentiation, hematopoiesis, and various other functions. It is functionally associated with a number of inflammatory pathologies including rheumatoid arthritis and inflammatory bowel ... ...

Abstract	GM-CSF is a potent inflammatory cytokine regulating myeloid cell differentiation, hematopoiesis, and various other functions. It is functionally associated with a number of inflammatory pathologies including rheumatoid arthritis and inflammatory bowel disease. GM-CSF has been found to promote NLRP3-dependent IL-1β secretion, which may have a significant role in driving inflammatory pathologies. However, the molecular mechanisms remain unknown. Here, we show that GM-CSF induces IL-1β secretion through a ROS-dependent pathway. TNF is required for reactive oxygen species (ROS) generation that strikingly does not promote NLRP3 activation, but instead drives ubiquitylation of IL-1β, promoting its cleavage through basal NRLP3 activity. GM-CSF regulates this pathway through suppression of antioxidant responses via preventing upregulation of NRF2. Thus, the pro-inflammatory effect of GM-CSF on IL-1β is through suppression of antioxidant responses, which leads to ubiquitylation of IL-1β and enhanced processing. This study highlights the role of metabolic regulation of inflammatory signaling and reveals a novel mechanism for GM-CSF to promote inflammation.
MeSH term(s)	Antioxidants/pharmacology ; Cells, Cultured ; Down-Regulation ; Granulocyte-Macrophage Colony-Stimulating Factor/genetics ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; Inflammasomes/metabolism ; Interleukin-1beta/genetics ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; Reactive Oxygen Species/metabolism
Chemical Substances	Antioxidants ; Inflammasomes ; Interleukin-1beta ; NF-E2-Related Factor 2 ; NLR Family, Pyrin Domain-Containing 3 Protein ; Reactive Oxygen Species ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
Language	English
Publishing date	2022-06-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.202154226
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Zs.A 5433: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Mitochondrial Metabolomics of Sym1-Depleted Yeast Cells Revealed Them to Be Lysine Auxotroph.

Lagies, Simon / Pan, Daqiang / Mohl, Daniel A / Plattner, Dietmar A / Gentle, Ian E / Kammerer, Bernd

Cells

2023 Volume 12, Issue 5

Abstract: Metabolomics has expanded from cellular to subcellular level to elucidate subcellular compartmentalization. By applying isolated mitochondria to metabolome analysis, the hallmark of mitochondrial metabolites has been unraveled, showing compartment- ... ...

Abstract	Metabolomics has expanded from cellular to subcellular level to elucidate subcellular compartmentalization. By applying isolated mitochondria to metabolome analysis, the hallmark of mitochondrial metabolites has been unraveled, showing compartment-specific distribution and regulation of metabolites. This method was employed in this work to study a mitochondrial inner membrane protein Sym1, whose human ortholog MPV17 is related to mitochondria DNA depletion syndrome. Gas chromatography-mass spectrometry-based metabolic profiling was combined with targeted liquid chromatography-mass spectrometry analysis to cover more metabolites. Furthermore, we applied a workflow employing ultra-high performance liquid chromatography-quadrupole time of flight mass spectrometry with a powerful chemometrics platform, focusing on only significantly changed metabolites. This workflow highly reduced the complexity of acquired data without losing metabolites of interest. Consequently, forty-one novel metabolites were identified in addition to the combined method, of which two metabolites, 4-guanidinobutanal and 4-guanidinobutanoate, were identified for the first time in
MeSH term(s)	Humans ; Lysine/metabolism ; Membrane Proteins/metabolism ; Metabolomics/methods ; Mitochondria/metabolism ; Saccharomyces cerevisiae/metabolism
Chemical Substances	Lysine (K3Z4F929H6) ; Membrane Proteins ; SYM1 protein, S cerevisiae
Language	English
Publishing date	2023-02-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12050692
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Article ; Online: Chlamydia trachomatis inhibits apoptosis in infected cells by targeting the pro-apoptotic proteins Bax and Bak.

Waguia Kontchou, Collins / Gentle, Ian E / Weber, Arnim / Schoeniger, Axel / Edlich, Frank / Häcker, Georg

Cell death and differentiation

2022 Volume 29, Issue 10, Page(s) 2046–2059

Abstract: Apoptosis acts in defense against microbial infection, and many infectious agents have developed strategies to inhibit host cell apoptosis. The human pathogen Chlamydia trachomatis (Ctr) is an obligate intracellular bacterium that strongly inhibits ... ...

Abstract	Apoptosis acts in defense against microbial infection, and many infectious agents have developed strategies to inhibit host cell apoptosis. The human pathogen Chlamydia trachomatis (Ctr) is an obligate intracellular bacterium that strongly inhibits mitochondrial apoptosis of its human host cell but there is no agreement how the bacteria achieve this. We here provide a molecular analysis of chlamydial apoptosis-inhibition in infected human cells and demonstrate that the block of apoptosis occurs during the activation of the effectors of mitochondrial apoptosis, Bak and Bax. We use small-molecule Bcl-2-family inhibitors and gene targeting to show that previous models cannot explain the anti-apoptotic effect of chlamydial infection. Although the anti-apoptotic Bcl-2-family protein Mcl-1 was strongly upregulated upon infection, Mcl-1-deficient cells and cells where Mcl-1 was pharmacologically inactivated were still protected. Ctr-infection could inhibit both Bax- and Bak-induced apoptosis. Apoptotic Bax-oligomerization and association with the outer mitochondrial membrane was reduced upon chlamydial infection. Infection further inhibited apoptosis induced conformational changes of Bak, as evidenced by changes to protease sensitivity, oligomerization and release from the mitochondrial porin VDAC2. Mitochondria isolated from Ctr-infected cells were protected against the pro-apoptotic Bcl-2-family proteins Bim and tBid but this protection was lost upon protease digestion. However, the protective effect of Ctr-infection was reduced in cells lacking the Bax/Bak-regulator VDAC2. We further found that OmpA, a porin of the outer membrane of Ctr, associated upon experimental expression with mitochondria and inhibited apoptosis, phenocopying the effect of the infection. These results identify a novel way of apoptosis inhibition, involving only the most downstream modulator of mitochondrial apoptosis and suggest that Chlamydia has a protein dedicated to the inhibition of apoptosis to secure its survival in human cells.
MeSH term(s)	Apoptosis/physiology ; Apoptosis Regulatory Proteins/metabolism ; Chlamydia trachomatis ; Humans ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Peptide Hydrolases ; Proto-Oncogene Proteins c-bcl-2/metabolism ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; bcl-2-Associated X Protein/metabolism
Chemical Substances	Apoptosis Regulatory Proteins ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2 ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-2-Associated X Protein ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2022-04-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-022-00995-0
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Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA).

Klaas, Lioba / Vier, Juliane / Gentle, Ian E / Häcker, Georg / Kirschnek, Susanne

Cell death & disease

2021 Volume 12, Issue 11, Page(s) 1011

Abstract: Regulated cell death frequently occurs upon infection by intracellular pathogens, and extent and regulation is often cell-type-specific. We aimed to identify the cell death-signaling pathways triggered in macrophages by infection with modified vaccinia ... ...

Abstract	Regulated cell death frequently occurs upon infection by intracellular pathogens, and extent and regulation is often cell-type-specific. We aimed to identify the cell death-signaling pathways triggered in macrophages by infection with modified vaccinia virus Ankara (MVA), an attenuated strain of vaccinia virus used in vaccination. While most target cells seem to be protected by antiapoptotic proteins encoded in the MVA genome, macrophages die when infected with MVA. We targeted key signaling components of specific cell death-pathways and pattern recognition-pathways using genome editing and small molecule inhibitors in an in vitro murine macrophage differentiation model. Upon infection with MVA, we observed activation of mitochondrial and death-receptor-induced apoptosis-pathways as well as the necroptosis-pathway. Inhibition of individual pathways had a little protective effect but led to compensatory death through the other pathways. In the absence of mitochondrial apoptosis, autocrine/paracrine TNF-mediated apoptosis and, in the absence of caspase-activity, necroptosis occurred. TNF-induction depended on the signaling molecule STING, and MAVS and ZBP1 contributed to MVA-induced apoptosis. The mode of cell death had a substantial impact on the cytokine response of infected cells, indicating that the immunogenicity of a virus may depend not only on its PAMPs but also on its ability to modulate individual modalities of cell death. These findings provide insights into the diversity of cell death-pathways that an infection can trigger in professional immune cells and advance our understanding of the intracellular mechanisms that govern the immune response to a virus.
MeSH term(s)	Animals ; Cell Death/genetics ; Humans ; Macrophages/metabolism ; Mice ; Signal Transduction ; Vaccines, DNA/therapeutic use ; Vaccinia virus/metabolism ; Viral Vaccines/therapeutic use
Chemical Substances	MVA vaccine ; Vaccines, DNA ; Viral Vaccines
Language	English
Publishing date	2021-10-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-021-04286-3
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Article: New perspectives in TNF-R1-induced NF-κB signaling.

Gentle, Ian E / Silke, John

Advances in experimental medicine and biology

2011 Volume 691, Page(s) 79–88

MeSH term(s)	Amino Acid Sequence ; Animals ; Cell Death ; Humans ; Inhibitor of Apoptosis Proteins/metabolism ; Mice ; Molecular Sequence Data ; NF-kappa B/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Receptors, Tumor Necrosis Factor, Type I/metabolism ; Signal Transduction ; TNF Receptor-Associated Factor 2/chemistry ; TNF Receptor-Associated Factor 2/metabolism ; Tumor Necrosis Factors/metabolism ; Ubiquitination
Chemical Substances	Inhibitor of Apoptosis Proteins ; NF-kappa B ; Receptors, Tumor Necrosis Factor, Type I ; TNF Receptor-Associated Factor 2 ; Tumor Necrosis Factors ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2011
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-1-4419-6612-4_8
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Article ; Online: Infection of epithelial cells with Chlamydia trachomatis inhibits TNF-induced apoptosis at the level of receptor internalization while leaving non-apoptotic TNF-signalling intact.

Waguia Kontchou, Collins / Tzivelekidis, Tina / Gentle, Ian E / Häcker, Georg

Cellular microbiology

2016 Volume 18, Issue 11, Page(s) 1583–1595

Abstract: Chlamydia trachomatis is an obligate intracellular bacterial pathogen of medical importance. C. trachomatis develops inside a membranous vacuole in the cytosol of epithelial cells but manipulates the host cell in numerous ways. One prominent effect of ... ...

Abstract	Chlamydia trachomatis is an obligate intracellular bacterial pathogen of medical importance. C. trachomatis develops inside a membranous vacuole in the cytosol of epithelial cells but manipulates the host cell in numerous ways. One prominent effect of chlamydial infection is the inhibition of apoptosis in the host cell, but molecular aspects of this inhibition are unclear. Tumour necrosis factor (TNF) is a cytokine with important roles in immunity, which is produced by immune cells in chlamydial infection and which can have pro-apoptotic and non-apoptotic signalling activity. We here analysed the signalling through TNF in cells infected with C. trachomatis. The pro-apoptotic signal of TNF involves the activation of caspase-8 and is controlled by inhibitor of apoptosis proteins. We found that in C. trachomatis-infected cells, TNF-induced apoptosis was blocked upstream of caspase-8 activation even when inhibitor of apoptosis proteins were inhibited or the inhibitor of caspase-8 activation, cFLIP, was targeted by RNAi. However, when caspase-8 was directly activated by experimental over-expression of its upstream adapter Fas-associated protein with death domain, C. trachomatis was unable to inhibit apoptosis. Non-apoptotic TNF-signalling, particularly the activation of NF-κB, initiates at the plasma membrane, while the activation of caspase-8 and pro-apoptotic signalling occur subsequently to internalization of TNF receptor and the formation of a cytosolic signalling complex. In C. trachomatis-infected cells, NF-κB activation through TNF was unaffected, while the internalization of the TNF-TNF-receptor complex was blocked, explaining the lack of caspase-8 activation. These results identify a dichotomy of TNF signalling in C. trachomatis-infected cells: Apoptosis is blocked at the internalization of the TNF receptor, but non-apoptotic signalling through this receptor remains intact, permitting a response to this cytokine at sites of infection.
MeSH term(s)	Apoptosis ; Caspase 3/metabolism ; Caspase 8/metabolism ; Chlamydia trachomatis/physiology ; Epithelial Cells/microbiology ; Epithelial Cells/physiology ; HEK293 Cells ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; NF-kappa B/metabolism ; Protein Transport ; Receptors, Tumor Necrosis Factor, Type I/metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha/physiology ; bcl-2-Associated X Protein/metabolism
Chemical Substances	BAX protein, human ; NF-kappa B ; Receptors, Tumor Necrosis Factor, Type I ; TNF protein, human ; Tumor Necrosis Factor-alpha ; bcl-2-Associated X Protein ; CASP3 protein, human (EC 3.4.22.-) ; CASP8 protein, human (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspase 8 (EC 3.4.22.-)
Language	English
Publishing date	2016-11
Publishing country	England
Document type	Journal Article
ZDB-ID	1468320-9
ISSN	1462-5822 ; 1462-5814
ISSN (online)	1462-5822
ISSN	1462-5814
DOI	10.1111/cmi.12598
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Article: TIRâdomainâcontaining adapterâinducing interferonâÎ² (TRIF) forms filamentous structures, whose proâapoptotic signalling is terminated by autophagy

Gentle, Ian E / Arlena Metz / Arnim Weber / Dale Porter / Georg HÃ¤cker / Kevin T. McHenry / Oliver Kretz

FEBS journal. 2017 July, v. 284, no. 13

2017

Abstract: The formation of amyloidâlike protein structures has recently emerged as a feature in signal transduction, particularly in innate immunity. These structures appear to depend on defined domains for their formation but likely also require dedicated ways ... ...

Abstract	The formation of amyloidâlike protein structures has recently emerged as a feature in signal transduction, particularly in innate immunity. These structures appear to depend on defined domains for their formation but likely also require dedicated ways to terminate signalling. We, here, define the innate immunity protein/Tollâlike receptor adaptor TIRâdomainâcontaining adapterâinducing interferonâÎ² (TRIF) as a novel platform of fibril formation and probe signal initiation through TRIF as well as its termination in Tollâlike receptor 3 (TLR3)âstimulated melanoma cells. A main signalling pathway triggered by TLR3 caused apoptosis, which was controlled by inhibitor of apoptosis proteins and was dependent on RIPK1 and independent of TNF. Using correlative electron/fluorescence microscopy, we visualised fibrillar structures formed through both Toll/interleukinâ1 receptor and RIP homotypic interacting motif regions of TRIF. We provide evidence that these fibrillary structures are active signalling platforms whose activity is terminated by autophagy. TRIFâsignalling enhanced autophagy, and fibrillary structures were partly contained within autophagosomes. Inhibition of autophagy increased levels of proâapoptotic TRIF complexes, leading to the accumulation of active caspaseâ8 and enhanced apoptosis while stimulation of autophagy reduced TRIFâdependent death. We conclude that proâdeath signals through TRIF are regulated by autophagy and propose that proâapoptotic signalling through TRIF/RIPK1/caspaseâ8 occurs in fibrillary platforms.
Keywords	apoptosis ; autophagy ; caspase-8 ; fluorescence microscopy ; interferon-beta ; melanoma ; protein structure ; signal transduction ; Toll-like receptor 3 ; tumor necrosis factors
Language	English
Dates of publication	2017-07
Size	p. 1987-2003.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.14091
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Article ; Online: Inhibitor of apoptosis proteins are required for effective fusion of autophagosomes with lysosomes.

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

Cell death & disease

2018 Volume 9, Issue 5, Page(s) 529

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 ... ...

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 term(s)	Animals ; Autophagosomes ; Baculoviral IAP Repeat-Containing 3 Protein/genetics ; Baculoviral IAP Repeat-Containing 3 Protein/metabolism ; Crohn Disease/genetics ; Crohn Disease/metabolism ; Crohn Disease/pathology ; Inhibitor of Apoptosis Proteins/genetics ; Inhibitor of Apoptosis Proteins/metabolism ; Lysosomes/genetics ; Lysosomes/metabolism ; Membrane Fusion ; Mice ; Mitochondrial Degradation
Chemical Substances	Birc4 protein, mouse ; Inhibitor of Apoptosis Proteins ; Baculoviral IAP Repeat-Containing 3 Protein (EC 2.3.2.27)
Language	English
Publishing date	2018-05-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-018-0508-y
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