TRIM41 is required to innate antiviral response by polyubiquitinating BCL10 and recruiting NEMO

Sensing of pathogenic nucleic acids by pattern recognition receptors (PRR) not only initiates anti-microbe defense but causes inflammatory and autoimmune diseases. E3 ubiquitin ligase(s) critical in innate response need to be further identified. Here we report that the tripartite motif-containing E3 ubiquitin ligase TRIM41 is required to innate antiviral response through facilitating pathogenic nucleic acids-triggered signaling pathway. TRIM41 deficiency impairs the production of inflammatory cytokines and type I interferons in macrophages after transfection with nucleic acid-mimics and infection with both DNA and RNA viruses. In vivo, TRIM41 deficiency leads to impaired innate response against viruses. Mechanistically, TRIM41 directly interacts with BCL10 (B cell lymphoma 10), a core component of CARD proteins-BCL10-MALT1 (CBM) complex, and modifies the Lys63-linked polyubiquitylation of BCL10, which, in turn, hubs NEMO for activation of NF-kappa B and TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) pathways. Our study suggests that TRIM41 is the potential universal E3 ubiquitin ligase responsible for Lys63 linkage of BCL10 during innate antiviral response, adding new insight into the molecular mechanism for the control of innate antiviral response.

Automated summary

TRIM41 plays a crucial role in innate antiviral response by facilitating pathogenic nucleic acids-triggered signaling pathway, interacting with BCL10 and modifying its polyubiquitylation to activate NF-kappa B and TBK1-IRF3 pathways. The deficiency of TRIM41 leads to impaired immune response against viruses, suggesting its potential as a universal E3 ubiquitin ligase in innate antiviral defense mechanism.