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Article ; Online: ATG16L1 WD40 domain-dependent IL10R (interleukin 10 receptor) signaling is insensitive to the T300A Crohn disease risk polymorphism.

Serramito-Gómez, Inmaculada / Terraza-Silvestre, Elena / Fernández-Cabrera, Álvaro / Villamuera, Raquel / Pimentel-Muiños, Felipe X

Autophagy

2022 Volume 18, Issue 12, Page(s) 3023–3030

Abstract: A coding allele ... ...

Abstract	A coding allele of
MeSH term(s)	Autophagy/genetics ; Autophagy-Related Proteins/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Crohn Disease/genetics ; Crohn Disease/metabolism ; Interleukin-10/metabolism ; Membrane Proteins/metabolism ; Nerve Tissue Proteins/metabolism ; Receptors, Interleukin-10/metabolism ; WD40 Repeats/genetics ; Humans
Chemical Substances	Autophagy-Related Proteins ; Carrier Proteins ; Interleukin-10 (130068-27-8) ; Membrane Proteins ; Nerve Tissue Proteins ; Receptors, Interleukin-10 ; ATG16L1 protein, human
Language	English
Publishing date	2022-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2022.2054241
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Article ; Online: Unconventional WD40 domain-dependent role of ATG16L1 in the regulation of IL10R (interleukin 10 receptor) endocytosis, trafficking and signaling.

Villamuera, Raquel / Fernández-Cabrera, Alvaro / Serramito-Gómez, Inmaculada / Terraza-Silvestre, Elena / Taouil, Rachid / Pimentel-Muiños, Felipe X

Autophagy

2021 Volume 17, Issue 9, Page(s) 2639–2641

Abstract: ATG16L1 is a critical mediator of macroautophagy/autophagy required for LC3 lipidation and autophagosome formation. However, ATG16L1 has a C-terminal domain including 7 WD40-type repetitions (WD40 domain, WDD) that is unnecessary for the conventional ... ...

Abstract	ATG16L1 is a critical mediator of macroautophagy/autophagy required for LC3 lipidation and autophagosome formation. However, ATG16L1 has a C-terminal domain including 7 WD40-type repetitions (WD40 domain, WDD) that is unnecessary for the conventional autophagic pathway. Instead, this domain mediates unconventional activities where LC3 is lipidated in atypical subcellular localizations unrelated to canonical double-membrane autophagosomes. The WDD provides a docking surface for molecules including a specific amino acid motif, thus engaging the LC3 lipidation capabilities of ATG16L1 in single-membrane structures. The physiological implications of such atypical activities are poorly characterized. In a recent report we described the improvement of the WDD-binding motif and the identification of transmembrane molecules that harbor this element in their intracellular region. One of them, IL10RB (interleukin 10 receptor subunit beta), binds the WDD after IL10 activation to facilitate endocytosis, early trafficking and signaling of IL10-IL10R complexes without influencing their degradation rate. These results reveal a novel unconventional role of ATG16L1 in cytokine signaling that does not entail a degradative purpose, thus contributing to catalog the physiological roles played by unconventional activities of the autophagic machinery.
MeSH term(s)	Autophagy/physiology ; Autophagy-Related Proteins/metabolism ; Endocytosis ; Receptors, Interleukin-10 ; WD40 Repeats
Chemical Substances	Autophagy-Related Proteins ; Receptors, Interleukin-10
Language	English
Publishing date	2021-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2021.1947606
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Article ; Online: Biochemical analyses reveal amino acid residues critical for cell cycle-dependent phosphorylation of human Cdc14A phosphatase by cyclin-dependent kinase 1.

Ovejero, Sara / Ayala, Patricia / Malumbres, Marcos / Pimentel-Muiños, Felipe X / Bueno, Avelino / Sacristán, María P

Scientific reports

2018 Volume 8, Issue 1, Page(s) 11871

Abstract: Cdc14 enzymes compose a family of highly conserved phosphatases that are present in a wide range of organisms, including yeast and humans, and that preferentially reverse the phosphorylation of Cyclin-Dependent Kinase (Cdk) substrates. The budding yeast ... ...

Abstract	Cdc14 enzymes compose a family of highly conserved phosphatases that are present in a wide range of organisms, including yeast and humans, and that preferentially reverse the phosphorylation of Cyclin-Dependent Kinase (Cdk) substrates. The budding yeast Cdc14 orthologue has essential functions in the control of late mitosis and cytokinesis. In mammals, however, the two Cdc14 homologues, Cdc14A and Cdc14B, do not play a prominent role in controlling late mitotic events, suggesting that some Cdc14 functions are not conserved across species. Moreover, in yeast, Cdc14 is regulated by changes in its subcellular location and by phosphorylation events. In contrast, little is known about the regulation of human Cdc14 phosphatases. Here, we have studied how the human Cdc14A orthologue is regulated during the cell cycle. We found that Cdc14A is phosphorylated on Ser411, Ser453 and Ser549 by Cdk1 early in mitosis and becomes dephosphorylated during late mitotic stages. Interestingly, in vivo and in vitro experiments revealed that, unlike in yeast, Cdk1-mediated phosphorylation of human Cdc14A did not control its catalytic activity but likely modulated its interaction with other proteins in early mitosis. These findings point to differences in Cdk1-mediated mechanisms of regulation between human and yeast Cdc14 orthologues.
MeSH term(s)	Amino Acids/metabolism ; Biochemical Phenomena/physiology ; CDC2 Protein Kinase/metabolism ; Cell Cycle/physiology ; Cell Cycle Proteins/metabolism ; Cell Line ; Cell Line, Tumor ; Cytokinesis/physiology ; Fungal Proteins/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Mitosis/physiology ; Phosphoric Monoester Hydrolases/metabolism ; Phosphorylation/physiology ; Yeasts/metabolism
Chemical Substances	Amino Acids ; Cell Cycle Proteins ; Fungal Proteins ; CDC2 Protein Kinase (EC 2.7.11.22) ; CDK1 protein, human (EC 2.7.11.22) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; CDC14A protein, human (EC 3.1.3.48)
Language	English
Publishing date	2018-08-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-30253-8
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Article ; Online: Unconventional autophagy mediated by the WD40 domain of ATG16L1 is derailed by the T300A Crohn disease risk polymorphism.

Serramito-Gómez, Inmaculada / Boada-Romero, Emilio / Pimentel-Muiños, Felipe X

Autophagy

2016 Volume 12, Issue 11, Page(s) 2254–2255

Abstract: A coding polymorphism of the critical autophagic effector ATG16L1 (T300A) increases the risk of Crohn disease, but how this mutation influences the function of ATG16L1 has remained unclear. In a recent report, we showed that the A300 allele alters the ... ...

Abstract	A coding polymorphism of the critical autophagic effector ATG16L1 (T300A) increases the risk of Crohn disease, but how this mutation influences the function of ATG16L1 has remained unclear. In a recent report, we showed that the A300 allele alters the ability of the C-terminal WD40 domain of ATG16L1 to interact with proteins containing a specific amino acid motif able to recognize this region. This defect impairs the capacity of the motif-containing transmembrane molecule TMEM59 to induce the unconventional autophagic labeling of the same single-membrane vesicles where this protein is located. Such alteration derails the intracellular trafficking of TMEM59 and the xenophagic response against bacterial infection. In contrast, canonical autophagy remains unaffected in the presence of ATG16L1
MeSH term(s)	Autophagy/genetics ; Autophagy-Related Proteins/chemistry ; Autophagy-Related Proteins/genetics ; Crohn Disease/genetics ; Genetic Predisposition to Disease ; Humans ; Mutation/genetics ; Polymorphism, Single Nucleotide/genetics ; Risk Factors ; WD40 Repeats
Chemical Substances	ATG16L1 protein, human ; Autophagy-Related Proteins
Language	English
Publishing date	2016-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2016.1216303
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Article ; Online: Selective autophagy against membranous compartments: Canonical and unconventional purposes and mechanisms.

Pimentel-Muiños, Felipe X / Boada-Romero, Emilio

Autophagy

2014 Volume 10, Issue 3, Page(s) 397–407

Abstract: Selective autophagic degradation of cellular components underlies many of the important physiological and pathological implications that autophagy has for mammalian cells. Cytoplasmic vesicles, just like other intracellular items, can be subjected to ... ...

Abstract	Selective autophagic degradation of cellular components underlies many of the important physiological and pathological implications that autophagy has for mammalian cells. Cytoplasmic vesicles, just like other intracellular items, can be subjected to conventional autophagic events where double-membrane autophagosomes specifically isolate and deliver them for lysosomal destruction. However, intracellular membranes appear to constitute common platforms for unconventional versions of the autophagic pathway, a notion that has become apparent during the past few years. For instance, in many cases of autophagy directed against bacterial phagosomes, subversion of the process results in multimembrane vacuoles that promote bacterial replication instead of the usual degradative outcome. In a different atypical modality, single-membrane vesicles can be labeled with LC3 to direct their contents for lysosomal degradation. In fact, single-membrane compartments of various kinds often provide an assembly site for the autophagic machinery to perform unanticipated nondegradative activities that range from localized secretion of lysosomal contents to melanosome function. Interestingly, many of these unconventional processes seem to be initiated through engagement of relevant nodes of the autophagic signaling network that, once activated, promote LC3 decoration of the targeted membrane, and some cases of inducer/receptor proteins that specifically engage those important signaling hubs have recently been described. Here we review the available examples of all autophagic variants involving membranous compartments, with a main focus on the more recently discovered unconventional phenomena where the usual degradation purpose of autophagy or its canonical mechanistic features are not completely conserved.
MeSH term(s)	Animals ; Autophagy/physiology ; Humans ; Intracellular Membranes/metabolism ; Microtubule-Associated Proteins/metabolism ; Phagosomes/metabolism ; Signal Transduction/physiology ; Vacuoles/metabolism
Chemical Substances	Microtubule-Associated Proteins
Language	English
Publishing date	2014-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.27244
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Article ; Online: The anti-inflammatory protein TNFAIP3/A20 binds the WD40 domain of ATG16L1 to control the autophagic response, NFKB/NF-κB activation and intestinal homeostasis.

Serramito-Gómez, Inmaculada / Boada-Romero, Emilio / Slowicka, Karolina / Vereecke, Lars / Van Loo, Geert / Pimentel-Muiños, Felipe X

Autophagy

2019 Volume 15, Issue 9, Page(s) 1657–1659

Abstract: The C-terminal domain of ATG16L1 includes 7 WD40-type repeats (WD40 domain, WDD) and is not required for canonical macroautophagy/autophagy. Instead, the WDD allows ATG16L1 to induce LC3/Atg8 lipidation in single-membrane compartments, although a ... ...

Abstract	The C-terminal domain of ATG16L1 includes 7 WD40-type repeats (WD40 domain, WDD) and is not required for canonical macroautophagy/autophagy. Instead, the WDD allows ATG16L1 to induce LC3/Atg8 lipidation in single-membrane compartments, although a detailed functional characterization of this region is still missing. In a recent report we identify the anti-inflammatory molecule TNFAIP3/A20 as a binding partner of the WDD. Such physical interaction allows mutual downregulation of the expression levels of both proteins, so that the absence of one of them causes upregulation of the other. This cross-regulation provides a molecular basis for a striking genetic interaction in mice where elimination of both molecules in the intestinal epithelium generates an aggressive inflammatory phenotype.
MeSH term(s)	Animals ; Anti-Inflammatory Agents ; Autophagy ; Autophagy-Related Proteins ; Carrier Proteins ; Homeostasis ; Mice ; NF-kappa B ; Tumor Necrosis Factor alpha-Induced Protein 3
Chemical Substances	Anti-Inflammatory Agents ; Atg16l1 protein, mouse ; Autophagy-Related Proteins ; Carrier Proteins ; NF-kappa B ; Tumor Necrosis Factor alpha-Induced Protein 3 (EC 3.4.19.12) ; Tnfaip3 protein, mouse (EC 3.4.22.-)
Language	English
Publishing date	2019-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2019.1628549
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Article ; Online: Regulation of cytokine signaling through direct interaction between cytokine receptors and the ATG16L1 WD40 domain.

Serramito-Gómez, Inmaculada / Boada-Romero, Emilio / Villamuera, Raquel / Fernández-Cabrera, Álvaro / Cedillo, José Luis / Martín-Regalado, Ángela / Carding, Simon / Mayer, Uli / Powell, Penny P / Wileman, Thomas / García-Higuera, Irene / Pimentel-Muiños, Felipe X

Nature communications

2020 Volume 11, Issue 1, Page(s) 5919

Abstract: ATG16L1, an autophagy mediator that specifies the site of LC3 lipidation, includes a C-terminal domain formed by 7 WD40-type repeats (WD40 domain, WDD), the function of which is unclear. Here we show that the WDD interacts with the intracellular domain ... ...

Abstract	ATG16L1, an autophagy mediator that specifies the site of LC3 lipidation, includes a C-terminal domain formed by 7 WD40-type repeats (WD40 domain, WDD), the function of which is unclear. Here we show that the WDD interacts with the intracellular domain of cytokine receptors to regulate their signaling output in response to ligand stimulation. Using a refined version of a previously described WDD-binding amino acid motif, here we show that this element is present in the intracellular domain of cytokine receptors. Two of these receptors, IL-10RB and IL-2Rγ, recognize the WDD through the motif and exhibit WDD-dependent LC3 lipidation activity. IL-10 promotes IL-10RB/ATG16L1 interaction through the WDD, and IL-10 signaling is suboptimal in cells lacking the WDD owing to delayed endocytosis and inefficient early trafficking of IL10/IL-10R complexes. Our data reveal WDD-dependent roles of ATG16L1 in the regulation of cytokine receptor trafficking and signaling, and provide a WDD-binding motif that might be used to identify additional WDD activators.
MeSH term(s)	Autophagy/physiology ; Autophagy-Related Proteins/metabolism ; Carrier Proteins/metabolism ; Cytokines/chemistry ; Cytokines/metabolism ; Endocytosis/physiology ; Humans ; Interleukin-10/metabolism ; Microtubule-Associated Proteins/metabolism ; Protein Transport ; Receptors, Cytokine/metabolism ; Receptors, Interleukin-10/metabolism ; Signal Transduction/physiology ; WD40 Repeats
Chemical Substances	ATG16L1 protein, human ; Autophagy-Related Proteins ; Carrier Proteins ; Cytokines ; Microtubule-Associated Proteins ; Receptors, Cytokine ; Receptors, Interleukin-10 ; Interleukin-10 (130068-27-8)
Language	English
Publishing date	2020-11-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-19670-4
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Article ; Online: BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1α.

Rodriguez, Diego A / Zamorano, Sebastian / Lisbona, Fernanda / Rojas-Rivera, Diego / Urra, Hery / Cubillos-Ruiz, Juan R / Armisen, Ricardo / Henriquez, Daniel R / Cheng, Emily H / Letek, Michal / Vaisar, Tomas / Irrazabal, Thergiory / Gonzalez-Billault, Christian / Letai, Anthony / Pimentel-Muiños, Felipe X / Kroemer, Guido / Hetz, Claudio

The EMBO journal

2021 Volume 40, Issue 18, Page(s) e109146

Language	English
Publishing date	2021-09-25
Publishing country	England
Document type	Published Erratum
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2021109146
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Zs.A 1808: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The T300A Crohn's disease risk polymorphism impairs function of the WD40 domain of ATG16L1.

Boada-Romero, Emilio / Serramito-Gómez, Inmaculada / Sacristán, María P / Boone, David L / Xavier, Ramnik J / Pimentel-Muiños, Felipe X

Nature communications

2016 Volume 7, Page(s) 11821

Abstract: A coding polymorphism of human ATG16L1 (rs2241880; T300A) increases the risk of Crohn's disease and it has been shown to enhance susceptibility of ATG16L1 to caspase cleavage. Here we show that T300A also alters the ability of the C-terminal WD40-repeat ... ...

Abstract	A coding polymorphism of human ATG16L1 (rs2241880; T300A) increases the risk of Crohn's disease and it has been shown to enhance susceptibility of ATG16L1 to caspase cleavage. Here we show that T300A also alters the ability of the C-terminal WD40-repeat domain of ATG16L1 to interact with an amino acid motif that recognizes this region. Such alteration impairs the unconventional autophagic activity of TMEM59, a transmembrane protein that contains the WD40 domain-binding motif, and disrupts its normal intracellular trafficking and its ability to engage ATG16L1 in response to bacterial infection. TMEM59-induced autophagy is blunted in cells expressing the fragments generated by caspase processing of the ATG16L1-T300A risk allele, whereas canonical autophagy remains unaffected. These results suggest that the T300A polymorphism alters the function of motif-containing molecules that engage ATG16L1 through the WD40 domain, either by influencing this interaction under non-stressful conditions or by inhibiting their downstream autophagic signalling after caspase-mediated cleavage.
MeSH term(s)	Alleles ; Amino Acid Motifs ; Animals ; Autophagy/genetics ; Autophagy-Related Proteins/chemistry ; Autophagy-Related Proteins/genetics ; Autophagy-Related Proteins/metabolism ; Carrier Proteins/chemistry ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Caspase 3/metabolism ; Crohn Disease/genetics ; Genetic Predisposition to Disease ; HCT116 Cells ; HEK293 Cells ; Humans ; Intracellular Space/metabolism ; Membrane Proteins/metabolism ; Mice ; Nerve Tissue Proteins/metabolism ; Peptides/metabolism ; Polymorphism, Single Nucleotide/genetics ; Protein Binding ; Protein Transport ; Risk Factors ; Staphylococcus aureus/physiology ; WD40 Repeats
Chemical Substances	ATG16L1 protein, human ; Atg16l1 protein, mouse ; Autophagy-Related Proteins ; Carrier Proteins ; Membrane Proteins ; Nerve Tissue Proteins ; Peptides ; TMEM59 protein, human ; Caspase 3 (EC 3.4.22.-)
Language	English
Publishing date	2016-06-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/ncomms11821
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Article ; Online: Physical and functional interaction between A20 and ATG16L1-WD40 domain in the control of intestinal homeostasis.

Slowicka, Karolina / Serramito-Gómez, Inmaculada / Boada-Romero, Emilio / Martens, Arne / Sze, Mozes / Petta, Ioanna / Vikkula, Hanna K / De Rycke, Riet / Parthoens, Eef / Lippens, Saskia / Savvides, Savvas N / Wullaert, Andy / Vereecke, Lars / Pimentel-Muiños, Felipe X / van Loo, Geert

Nature communications

2019 Volume 10, Issue 1, Page(s) 1834

Abstract: Prevention of inflammatory bowel disease (IBD) relies on tight control of inflammatory, cell death and autophagic mechanisms, but how these pathways are integrated at the molecular level is still unclear. Here we show that the anti-inflammatory protein ... ...

Abstract	Prevention of inflammatory bowel disease (IBD) relies on tight control of inflammatory, cell death and autophagic mechanisms, but how these pathways are integrated at the molecular level is still unclear. Here we show that the anti-inflammatory protein A20 and the critical autophagic mediator Atg16l1 physically interact and synergize to regulate the stability of the intestinal epithelial barrier. A proteomic screen using the WD40 domain of ATG16L1 (WDD) identified A20 as a WDD-interacting protein. Loss of A20 and Atg16l1 in mouse intestinal epithelium induces spontaneous IBD-like pathology, as characterized by severe inflammation and increased intestinal epithelial cell death in both small and large intestine. Mechanistically, absence of A20 promotes Atg16l1 accumulation, while elimination of Atg16l1 or expression of WDD-deficient Atg16l1 stabilizes A20. Collectively our data show that A20 and Atg16l1 cooperatively control intestinal homeostasis by acting at the intersection of inflammatory, autophagy and cell death pathways.
MeSH term(s)	Animals ; Autophagy/immunology ; Autophagy-Related Proteins ; Carrier Proteins/genetics ; Carrier Proteins/immunology ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Endoscopy ; Female ; Homeostasis/immunology ; Humans ; Inflammatory Bowel Diseases/diagnostic imaging ; Inflammatory Bowel Diseases/genetics ; Inflammatory Bowel Diseases/immunology ; Inflammatory Bowel Diseases/pathology ; Intestinal Mucosa/cytology ; Intestinal Mucosa/diagnostic imaging ; Intestinal Mucosa/immunology ; Intestinal Mucosa/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Protein Binding/immunology ; Proteomics ; Tumor Necrosis Factor alpha-Induced Protein 3/genetics ; Tumor Necrosis Factor alpha-Induced Protein 3/immunology ; Tumor Necrosis Factor alpha-Induced Protein 3/metabolism ; WD40 Repeats/genetics ; WD40 Repeats/immunology
Chemical Substances	Atg16l1 protein, mouse ; Autophagy-Related Proteins ; Carrier Proteins ; Tumor Necrosis Factor alpha-Induced Protein 3 (EC 3.4.19.12) ; Tnfaip3 protein, mouse (EC 3.4.22.-)
Language	English
Publishing date	2019-04-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-09667-z
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