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Published on: March 5, 2019
Porcine TRIM45 negatively regulates the RLR signaling pathway by targeting IKKε for protein degradation
Chenxi Li1, Jingjing Li2, Shiyu Wang2
1College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Comparative Medicine Research Institute, Yangzhou University, Yangzhou, 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, China.
Abstract:
The tripartite motif 45 (TRIM45) protein belongs to the RING-type E3 ubiquitin ligases and exerts multiple biological functions in cell signaling and inflammation regulation by catalyzing ubiquitination of adaptor proteins in the corresponding cascades. In the present work, we obtained the porcine TRIM45 (porTRIM45) coding sequence and examined its contribution to type I IFN induction. The open reading frame (ORF) encodes a 580-amino-acid polypeptide that shares 84.7-89.7% sequence identity with orthologs from human, mouse, and monkey. porTRIM45 harbors a RING domain, two B-box domains, a coiled-coil domain, and a FIL domain, and exhibits broad tissue distribution across porcine tissues. Functional analyses showed that porTRIM45 participates in modulating type I IFN production upon poly(I:C) stimulation. Mechanistically, porTRIM45 associates with porcine IκB kinase epsilon (IKKε) and promotes its K48-linked polyubiquitination for proteasomal degradation, consequently dampening RLRs signaling pathway. Additionally, we verified that the RING and FIL domains are indispensable for the E3 ligase function of porTRIM45. Collectively, our findings underscore the crucial role of porTRIM45 in IKKε-mediated innate immune signaling in pigs.
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