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Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2
Author(s) -
Chathuranga Kiramage,
Kim TaeHwan,
Lee Hyuncheol,
Park JunSeol,
Kim JaeHoon,
Chathuranga Wijesinghe A Gayan,
Ekanayaka Pathum,
Choi Youn Jung,
Lee ChulHo,
Kim ChulJoong,
Jung Jae U,
Lee JongSoo
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020105139
Subject(s) - library science , veterinary medicine , medicine , computer science
NF‐κB essential modulator (NEMO) is a key regulatory protein that functions during NF‐κB‐ 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 both in vitro and in 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.