The structural basis of TRIM25-mediated regulation of RIG-I
Yunlong Li, Siqi Wu, Xuyang Tian, Kong Chen, Wenbin Hong, Tianyichen Xiao, Songqing Wang, Zhiming Wei, Zhiming Su, Haixia Ren, Yunlong Song, Lichen Hu, Donghai Lin, Hongwei Yao, Jiahuai Han, Xueqin Chen, Tianwei Lin
Abstract
TRIM25, an E3 ligase, is an important regulator to modulate the functions of retinoic acid inducible gene-I (RIG-I) and other factors in innate immunity. Herein the structural interaction between the 2CARD domain of RIG-I and the PRYSPRY domain of TRIM25 was investigated by NMR, X-ray crystallography, computer-assisted modeling, and cell-based assays to elucidate the complex structure of PRYSPRY/2CARD. The interacting model indicated that docking of 2CARD onto PRYSPRY brought two RIG-I molecules into a close proximity to form a dimer. The attachment of a short ubiquitin chain covalently by the TRIM25's E3 ligase activity was favorable for tethering a neighboring RIG-I dimer to form the tetrameric RIG-I by noncovalent interactions. The data supported the notion that the TRIM25-RIG-I interaction was important to activate the RIG-I pathway to suppress the replication of RNA viruses, such as vesicular stomatitis virus. This work provides a structural rationale to delineate the underlying mechanism of TRIM25 regulation of RIG-I.