Abstract

Toll-like receptor (TLR) signaling is pivotal to innate and adaptive immune responses and must be tightly controlled. The mechanisms of TLR signaling have been the focus of extensive studies. Here we report that the tripartite-motif protein TRIM30, a RING protein, was induced by TLR agonists and interacted with the TAB2-TAB3-TAK1 adaptor-kinase complex involved in the activation of transcription factor NF-B. TRIM30 promoted the degradation of TAB2 and TAB3 and inhibited NF-B activation induced by TLR signaling. In vivo studies showed that transfected or transgenic mice overexpressing TRIM30 were more resistant to endotoxic shock. Consistent with that, in vivo 'knockdown' of TRIM30 mRNA by small interfering RNA impaired lipopolysaccharide-induced tolerance. Finally, expression of TRIM30 depended on NF-B activation. Our results collectively indicate that TRIM30 negatively regulates TLR-mediated NF-B activation by targeting degradation of TAB2 and TAB3 by a 'feedback' mechanism.

1. Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
2. Shanghai Medical College, Fudan University, Shanghai 200032, China.
3. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 31003, China.
4. Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China.
5. Immunology Division, E-institutes of Shanghai Universities, Shanghai 200025, China.
6. These authors contributed equally to this work.

Correspondence to: Bing Sun^1,4,5 e-mail: bsun@sibs.ac.cn

Correspondence to: Charlie Xiang³ e-mail: cxiang@zju.edu.cn

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