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The anti-inflammatory protein TNFAIP3/A20 binds the WD40 domain of ATG16L1 to control the autophagic response, NFKB/NF-kappa B activation and intestinal homeostasis

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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. In vitro studies reveal unexpected features of the functional interplay between ATG16L1 and TNFAIP3. ATG16L1 requires TNFAIP3 to sustain the canonical autophagic flux measured by SQSTM1/p62 degradation. The WDD mediates lysosomal degradation of TNFAIP3 promoted by ATG16L1, and also regulates the NFKB/NF-kappa B response. Therefore, our data reveal new roles of the WDD and TNFAIP3 in the regulation of autophagy, protein stability and inflammatory signaling. More generally, we identify the interaction between ATG16L1 and TNFAIP3 as a signaling hub that integrates different pathways with important implications for intestinal homeostasis.
Keywords
autophagy, inflammatory bowel disease (IBD), intestinal homeostasis, TNFAIP3, A20, WD40 domain (WDD)

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MLA
Serramito-Gomez, Inmaculada et al. “The Anti-inflammatory Protein TNFAIP3/A20 Binds the WD40 Domain of ATG16L1 to Control the Autophagic Response, NFKB/NF-kappa B Activation and Intestinal Homeostasis.” AUTOPHAGY 2019 : n. pag. Print.
APA
Serramito-Gomez, I., Boada-Romero, E., Slowicka, K., Vereecke, L., van Loo, G., & Pimentel-Muinos, F. X. (2019). The anti-inflammatory protein TNFAIP3/A20 binds the WD40 domain of ATG16L1 to control the autophagic response, NFKB/NF-kappa B activation and intestinal homeostasis. AUTOPHAGY. Philadelphia: Taylor & Francis Inc.
Chicago author-date
Serramito-Gomez, Inmaculada, Emilio Boada-Romero, Karolina Slowicka, Lars Vereecke, Geert van Loo, and Felipe X. Pimentel-Muinos. 2019. “The Anti-inflammatory Protein TNFAIP3/A20 Binds the WD40 Domain of ATG16L1 to Control the Autophagic Response, NFKB/NF-kappa B Activation and Intestinal Homeostasis.” Autophagy. Philadelphia: Taylor & Francis Inc.
Chicago author-date (all authors)
Serramito-Gomez, Inmaculada, Emilio Boada-Romero, Karolina Slowicka, Lars Vereecke, Geert van Loo, and Felipe X. Pimentel-Muinos. 2019. “The Anti-inflammatory Protein TNFAIP3/A20 Binds the WD40 Domain of ATG16L1 to Control the Autophagic Response, NFKB/NF-kappa B Activation and Intestinal Homeostasis.” Autophagy. Philadelphia: Taylor & Francis Inc.
Vancouver
1.
Serramito-Gomez I, Boada-Romero E, Slowicka K, Vereecke L, van Loo G, Pimentel-Muinos FX. The anti-inflammatory protein TNFAIP3/A20 binds the WD40 domain of ATG16L1 to control the autophagic response, NFKB/NF-kappa B activation and intestinal homeostasis. AUTOPHAGY. Philadelphia: Taylor & Francis Inc; 2019.
IEEE
[1]
I. Serramito-Gomez, E. Boada-Romero, K. Slowicka, L. Vereecke, G. van Loo, and F. X. Pimentel-Muinos, “The anti-inflammatory protein TNFAIP3/A20 binds the WD40 domain of ATG16L1 to control the autophagic response, NFKB/NF-kappa B activation and intestinal homeostasis,” AUTOPHAGY. Taylor & Francis Inc, Philadelphia, 2019.
@misc{8622873,
  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. In vitro studies reveal unexpected features of the functional interplay between ATG16L1 and TNFAIP3. ATG16L1 requires TNFAIP3 to sustain the canonical autophagic flux measured by SQSTM1/p62 degradation. The WDD mediates lysosomal degradation of TNFAIP3 promoted by ATG16L1, and also regulates the NFKB/NF-kappa B response. Therefore, our data reveal new roles of the WDD and TNFAIP3 in the regulation of autophagy, protein stability and inflammatory signaling. More generally, we identify the interaction between ATG16L1 and TNFAIP3 as a signaling hub that integrates different pathways with important implications for intestinal homeostasis.},
  author       = {Serramito-Gomez, Inmaculada and Boada-Romero, Emilio and Slowicka, Karolina and Vereecke, Lars and van Loo, Geert and Pimentel-Muinos, Felipe X.},
  issn         = {1554-8627},
  keywords     = {autophagy,inflammatory bowel disease (IBD),intestinal homeostasis,TNFAIP3,A20,WD40 domain (WDD)},
  language     = {eng},
  publisher    = {Taylor & Francis Inc},
  series       = {AUTOPHAGY},
  title        = {The anti-inflammatory protein TNFAIP3/A20 binds the WD40 domain of ATG16L1 to control the autophagic response, NFKB/NF-kappa B activation and intestinal homeostasis},
  url          = {http://dx.doi.org/10.1080/15548627.2019.1628549},
  year         = {2019},
}

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