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Non-proteolytic ubiquitination of OTULIN regulates NF-kappa B signaling pathway

文献类型： 外文期刊

作者： Zhao, Mengmeng 1 ; Song, Kun 1 ; Hao, Wenzhuo 1 ; Wang, Lingyan 1 ; Patil, Girish 1 ; Li, Qingmei 1 ; Xu, Lingling 1 ; Hu 1 ;

作者机构： 1.Oklahoma State Univ, Dept Physiol Sci, Ctr Vet Hlth Sci, Stillwater, OK 74078 USA

2.Henan Acad Agr Sci, Key Lab Anim Immunol, Zhengzhou, Peoples R China

3.Wuhan Univ, Med Res Inst, State Key Lab Virol, Wuhan, Peoples R China

4.Univ Luxembourg, Luxembourg Ctr Syst Biomed, Luxembourg, Luxembourg

5.Harvard Med Sch, Dept Immunol, Boston, MA 02115 USA

关键词： NF-kappa B; LUBAC; TNF; linear ubiquitination; TRIM; proteomics

期刊名称：JOURNAL OF MOLECULAR CELL BIOLOGY （ 影响因子：6.216； 五年影响因子：6.688 ）

ISSN： 1674-2788

年卷期： 2020 年 12 卷 3 期

页码：

收录情况： SCI

摘要： NF-kappa B signaling regulates diverse processes such as cell death, inflammation, immunity, and cancer. The activity of NF-kappa B is controlled by methionine 1-linked linear polyubiquitin, which is assembled by the linear ubiquitin chain assembly complex (LUBAC) and the ubiquitin-conjugating enzyme UBE2L3. Recent studies found that the deubiquitinase OTULIN breaks the linear ubiquitin chain, thus inhibiting NF-kappa B signaling. Despite the essential role of OTULIN in NF-kappa B signaling has been established, the regulatory mechanism for OTULIN is not well elucidated. To discover the potential regulators of OTULIN, we analyzed the OTULIN protein complex by proteomics and revealed several OTULIN-binding proteins, including LUBAC and tripartite motif-containing protein 32 (TRIM32). TRIM32 is known to activate NF-kappa B signaling, but the mechanism is not clear. Genetic complement experiments found that TRIM32 is upstream of OTULIN and TRIM32-mediated NF-kappa B activation is dependent on OTULIN. Mutagenesis of the E3 ligase domain showed that the E3 ligase activity is essential for TRIM32-mediated NF-kappa B activation. Further experiments found that TRIM32 conjugates polyubiquitin onto OTULIN and the polyubiquitin blocks the interaction between HOIP and OTULIN, thereby activating NF-kappa B signaling. Taken together, we report a novel regulatory mechanism by which TRIM32-mediated non-proteolytic ubiquitination of OTULIN impedes the access of OTULIN to the LUBAC and promotes NF-kappa B activation.

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