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

被引:18
作者
Serramito-Gomez, Inmaculada [1 ]
Boada-Romero, Emilio [1 ]
Slowicka, Karolina [2 ,3 ]
Vereecke, Lars [2 ,4 ]
Van Loo, Geert [2 ,3 ]
Pimentel-Muinos, Felipe X. [1 ]
机构
[1] Univ Salamanca, Inst Biol Mol & Celular Canc, CSIC, Ctr Invest Canc, Campus Miguel de Unamuno, Salamanca 37007, Spain
[2] VIB Ctr Inflammat Res, Ghent, Belgium
[3] Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium
[4] Univ Ghent, Dept Rheumatol, Ghent, Belgium
关键词
autophagy; inflammatory bowel disease (IBD); intestinal homeostasis; TNFAIP3; A20; WD40 domain (WDD);
D O I
10.1080/15548627.2019.1628549
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:1657 / 1659
页数:3
相关论文
共 1 条
[1]   Physical and functional interaction between A20 and ATG16L1-WD40 domain in the control of intestinal homeostasis [J].
Slowicka, Karolina ;
Serramito-Gomez, 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-Muinos, Felipe X. ;
van Loo, Geert .
NATURE COMMUNICATIONS, 2019, 10 (1)