한빛사 논문
Kiramage Chathuranga1,‡, Tae‐Hwan Kim1,2,‡, Hyuncheol Lee1,3,‡, Jun‐Seol Park1,‡, Jae‐Hoon Kim4, Wijesinghe A Gayan Chathuranga1, Pathum Ekanayaka1, Youn Jung Choi5, Chul‐Ho Lee4, Chul‐Joong Kim1, Jae U Jung5 and Jong‐Soo Lee*,1
1College of Veterinary Medicine, Chungnam National University, Daejeon, Korea
2Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
3California Institute for Quantitative Biosciences, University of California, Berkeley, CA, USA
4Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Daejeon, Korea
5Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
‡These authors contributed equally to this work
*Corresponding author
Abstract
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.
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