TRIM41 is required to innate antiviral response by polyubiquitinating BCL10 and recruiting NEMO
Authors: Jianjun Jia
Yan Gu
Xuelian Li
Taoyong Chen
Qian Fang
Jiaying Huang
Mingjin Yang
Zheng Li
Xuetao Cao
Zhou Yu
Journal: Signal Transduction and Targeted Therapy (2021)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Pathogenic nucleic acids; pattern recognition receptors; E3 ubiquitin ligase; TRIM41; innate antiviral response
Affiliations: Center for Systems Medicine, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China., Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, China., National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China., Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China., National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China. ., Center for Systems Medicine, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China. ., Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, China. ., Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China. ., College of Life Science, Nankai University, Tianjin, 300071, China. .

Abstract:  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-Œ∫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. 

Retracted: No

PubPeer comments:
  , 
 Dear Artedidraco Skottsbergi: Your question about the different expression pattern of TRIM41 between Fig S1b and Fig 3a is not correct. In Fig. S1b, endogenous TRIM41 in peritoneal macrophages was downregulated after virus infection for 4h, as examined by WB analysis of whole cell extracts. But, Fig. 3a showed the overexpression efficiency of Flag-TRIM41 and Myc-STING in HEK293T cells before the virus infection. The annotations of u201cPBS, VSV, HSVu201d in lower panel of Fig 3a indicated the subsequent treatments for Fig 3e. Please check the figure legends, in which we have clearly described the experimental procedure in the legend of Fig 3a: u201cHEK293T cells were cotransfected with mock or Flag-tagged TRIM41 (10, 50, or 100 ng) vectors, vectors for PRR adaptors (100 ng MAVS or STING), and reporter vectors. 48 h later, the expression of TRIM41-Flag and STING-Myc was examined by Western blotting (a). Then the cells were infected with (e) or without (bu2013d) VSV (MOI = 1) or HSV-1 (MOI = 5) for 4 h, and the luciferase activity was determinedu201d. Best, Co-corresponding Author: Taoyong Chen , 
 Fig.3A is recombinant TRIM41; Fig.S1B is endogenous TRIM41. ,