Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2

被引：21

作者：

Chathuranga, Kiramage ^{[1
]}

Kim, Tae-Hwan ^{[1
,2
]}

Lee, Hyuncheol ^{[1
,3
]}

Park, Jun-Seol ^{[1
]}

Kim, Jae-Hoon ^{[4
]}

Chathuranga, Wijesinghe A. Gayan ^{[1
]}

Ekanayaka, Pathum ^{[1
]}

Choi, Youn Jung ^{[5
]}

Lee, Chul-Ho ^{[4
]}

Kim, Chul-Joong ^{[1
]}

Jung, Jae U. ^{[5
]}

Lee, Jong-Soo ^{[1
]}

机构：

[1] Chungnam Natl Univ, Coll Vet Med, Daejeon, South Korea

[2] Korea Res Inst Biosci & Biotechnol, Infect Dis Res Ctr, Daejeon, South Korea

[3] Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA

[4] Univ Sci & Technol UST, Korea Res Inst Biosci & Biotechnol, Lab Anim Resource Ctr, Daejeon, South Korea

[5] Univ Southern Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90007 USA

来源：

EMBO JOURNAL | 2020年 / 39卷 / 21期

基金：

新加坡国家研究基金会;

关键词：

innate immunity; MARCH2; NEMO; ubiquitination; KAPPA-B PATHWAY; INNATE IMMUNITY; IKK-EPSILON; PROTEIN; ACTIVATION; EXPRESSION; INFECTION; CELLS; IRF3; IDENTIFICATION;

D O I：

10.15252/embj.2020105139

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

NF-kappa B essential modulator (NEMO) is a key regulatory protein that functions during NF-kappa B- and interferon-mediated signaling in response to extracellular stimuli and pathogen infections. Tight regulation of NEMO is essential for host innate immune responses and for maintenance of homeostasis. Here, we report that the E3 ligase MARCH2 is a novel negative regulator of NEMO-mediated signaling upon bacterial or viral infection. MARCH2 interacted directly with NEMO during the late phase of infection and catalyzed K-48-linked ubiquitination of Lys326 on NEMO, which resulted in its degradation. Deletion of MARCH2 resulted in marked resistance to bacterial/viral infection, along with increased innate immune responses bothin vitroandin vivo. In addition, MARCH2(-/-)mice were more susceptible to LPS challenge due to massive production of cytokines. Taken together, these findings provide new insight into the molecular regulation of NEMO and suggest an important role for MARCH2 in homeostatic control of innate immune responses.

引用

页数：18

共 71 条

[1] The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO [J].