Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities.
Nat Immunol
; 21(4): 381-387, 2020 04.
Article
in En
| MEDLINE
| ID: mdl-32205881
ABSTRACT
Protein ubiquitination regulates protein stability and modulates the composition of signaling complexes. A20 is a negative regulator of inflammatory signaling, but the molecular mechanisms involved are ill understood. Here, we generated Tnfaip3 gene-targeted A20 mutant mice bearing inactivating mutations in the zinc finger 7 (ZnF7) and ZnF4 ubiquitin-binding domains, revealing that binding to polyubiquitin is essential for A20 to suppress inflammatory disease. We demonstrate that a functional ZnF7 domain was required for recruiting A20 to the tumor necrosis factor receptor 1 (TNFR1) signaling complex and to suppress inflammatory signaling and cell death. The combined inactivation of ZnF4 and ZnF7 phenocopied the postnatal lethality and severe multiorgan inflammation of A20-deficient mice. Conditional tissue-specific expression of mutant A20 further revealed the key role of ubiquitin-binding in myeloid and intestinal epithelial cells. Collectively, these results demonstrate that the anti-inflammatory and cytoprotective functions of A20 are largely dependent on its ubiquitin-binding properties.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tumor Necrosis Factor alpha-Induced Protein 3
/
Inflammation
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Immunol
Journal subject:
ALERGIA E IMUNOLOGIA
Year:
2020
Type:
Article
Affiliation country:
Belgium