RNF138 inhibits late inflammatory gene transcription through degradation of SMARCC1 of the SWI/SNF complex

As one of the core components of the switching or sucrose non-fermentable (SWI/SNF) complex, SMARCC1 (BAF155, SRG3) plays essential roles in activation of late inflammatory genes in response to microbial challenge. However, little is known about the mechanism of how SMARCC1 regulates the inflammatory innate response. Via functional screening, we identify the nuclear E3 ubiquitin ligase RNF138 as a negative regulator in the inflammatory innate response and show that RNF138 interacts with SMARCC1 and mediates its K48 -linked polyubiquitination at position Lys643 and proteasomal degradation. As a result, the catalytic activity of RNF138 fine-tunes the kinetics of late inflammatory gene transcription by inhibiting chromatin remodeling at SWI/SNF-regulated gene loci. Reduced RNF138 and increased SMARCC1 in monocytes of rheumatoid arthritis patients are observed. These results provide mechanistic insight into the interplay among nucleo-some remodeling, inflammation, and ubiquitylation and underscore the important role of the E3 ubiquitin ligases in controlling the extent and duration of inflammatory responses.

Automated summary

As one of the core components of the SWI/SNF complex, SMARCC1 plays a crucial role in activating late inflammatory genes. This study reveals that the nuclear E3 ubiquitin ligase RNF138 negatively regulates the inflammatory response by interacting and degrading SMARCC1. The findings uncover the mechanism of nucleosome remodeling, inflammation, and ubiquitination, highlighting the important role of E3 ubiquitin ligases in controlling inflammatory responses.