title: MKRN2 is a novel ubiquitin E3 ligase for the p65 subunit of NF-κB and negatively regulates inflammatory responses.
abstract: Activation of NF-κB transcription factor is strictly regulated to prevent excessive inflammatory responses leading to immunopathology. However, it still remains unclear how NF-κB activation is negatively controlled. The PDZ-LIM domain-containing protein PDLIM2 is a nuclear ubiquitin E3 ligase targeting the p65 subunit of NF-κB for degradation, thus terminating NF-κB-mediated inflammation. Using yeast two-hybrid screening, we sought to isolate PDLIM2-interacting proteins that are critical for suppressing NF-κB signaling. Here we identified MKRN2, a RING finger domain-containing protein that belongs to the makorin ring finger protein gene family, as a novel p65 ubiquitin E3 ligase. MKRN2 bound to p65 and promoted the polyubiquitination and proteasome-dependent degradation of p65 through the MKRN2 RING finger domain, thereby suppressing p65-mediated NF-κB transactivation. Notably, MKRN2 and PDLIM2 synergistically promote polyubiquitination and degradation of p65. Consistently, MKRN2 knockdown in dendritic cells resulted in larger amounts of nuclear p65 and augmented production of proinflammatory cytokines in responses to innate stimuli. These results delineate a novel role of MKRN2 in negatively regulating NF-κB-mediated inflammatory responses, cooperatively with PDLIM2.
authors.affiliation: Laboratory for Inflammatory Regulation, RIKEN Center for Integrative Medical Sciences (IMS), RIKEN Research Center for Allergy and Immunology (RCAI), Yokohama, Kanagawa 230-0045, Japan.|School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, Japan.
authors.forename: Chanyoung
authors.initials: C
authors.lastname: Shin
authors.affiliation: School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, Japan.
authors.forename: Yuma
authors.initials: Y
authors.lastname: Ito
authors.affiliation: School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Ichikawa
authors.affiliation: School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, Japan.
authors.forename: Makio
authors.initials: M
authors.lastname: Tokunaga
authors.affiliation: School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Sakata-Sogawa
authors.affiliation: Laboratory for Inflammatory Regulation, RIKEN Center for Integrative Medical Sciences (IMS), RIKEN Research Center for Allergy and Immunology (RCAI), Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D060588:LIM Domain Proteins / Q000378:metabolism; D051379:Mice; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism*; D059748:Proteolysis; D054829:RING Finger Domains; D012261:Ribonucleoproteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C512670:MKRN2 protein, human; C512678:Mkrn2 protein, mouse; C508508:Pdlim2 protein, mouse; D021122:Protein Subunits; C498143:RELA protein, human; D012261:Ribonucleoproteins; D051996:Transcription Factor RelA; D025821:Polyubiquitin