2. Academic Validation
  3. Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2

Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2

  • EMBO J. 2020 Nov 2;39(21):e105139. doi: 10.15252/embj.2020105139.
Kiramage Chathuranga # 1,  Tae-Hwan Kim # 1 2,  Hyuncheol Lee # 1 3,  Jun-Seol Park # 1,  Jae-Hoon Kim 4,  Wijesinghe A Gayan Chathuranga 1,  Pathum Ekanayaka 1,  Youn Jung Choi 5,  Chul-Ho Lee 4,  Chul-Joong Kim 1,  Jae U Jung 5,  Jong-Soo Lee 1
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Chungnam National University, Daejeon, Korea.
  • 2 Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
  • 3 California Institute for Quantitative Biosciences, University of California, Berkeley, CA, USA.
  • 4 Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Daejeon, Korea.
  • 5 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • # Contributed equally.
PMID: 32935379 DOI: 10.15252/embj.2020105139
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.

Keywords

MARCH2; NEMO; innate immunity; ubiquitination.

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