title: Negative regulation of NF-κB activity by brain-specific TRIpartite Motif protein 9.
abstract: The TRIpartite Motif (TRIM) family of RING-domain-containing proteins participate in a variety of cellular functions. The β-transducin repeat-containing protein (β-TrCP), a component of the Skp-Cullin-F-box-containing (SCF) E3 ubiquitin ligase complex, recognizes the NF-κB inhibitor IκBα and precursor p100 for proteasomal degradation and processing, respectively. β-TrCP thus plays a critical role in both canonical and non-canonical NF-κB activation. Here we report that TRIM9 is a negative regulator of NF-κB activation. Interaction between the phosphorylated degron motif of TRIM9 and the WD40 repeat region of β-TrCP prevented β-TrCP from binding its substrates, stabilizing IκBα and p100 and thereby blocking NF-κB activation. Consequently, expression or depletion of the TRIM9 gene significantly affected NF-κB-induced inflammatory cytokine production. This study not only elucidates a mechanism for TRIM9-mediated regulation of the β-TrCP SCF complex activity but also identifies TRIM9 as a brain-specific negative regulator of the NF-κB pro-inflammatory signalling pathway.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, HMR Room 401, 2011 Zonal Avenue, Los Angeles, California 90033, USA.
authors.forename: Mude
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, HMR Room 401, 2011 Zonal Avenue, Los Angeles, California 90033, USA.
authors.forename: Hyelim
authors.initials: H
authors.lastname: Cho
authors.affiliation: 1] Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, HMR Room 401, 2011 Zonal Avenue, Los Angeles, California 90033, USA [2] Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 1 Hoegl-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Inn
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology, 373-1 Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic of Korea.
authors.forename: Aerin
authors.initials: A
authors.lastname: Yang
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, HMR Room 401, 2011 Zonal Avenue, Los Angeles, California 90033, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, HMR Room 401, 2011 Zonal Avenue, Los Angeles, California 90033, USA.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Liang
authors.affiliation: 1] Max F. Perutz Laboratories, Dr-Bohr-Gasse 9, Wien, Vienna 1030, Austria [2] Department of Microbiology, Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Gijs A
authors.initials: GA
authors.lastname: Versteeg
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, HMR Room 401, 2011 Zonal Avenue, Los Angeles, California 90033, USA.
authors.forename: Samad
authors.initials: S
authors.lastname: Amini-Bavil-Olyaee
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, HMR Room 401, 2011 Zonal Avenue, Los Angeles, California 90033, USA.
authors.forename: Lai-Yee
authors.initials: LY
authors.lastname: Wong
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, HMR Room 401, 2011 Zonal Avenue, Los Angeles, California 90033, USA.
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology, 373-1 Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic of Korea.
authors.forename: Hee-Sung
authors.initials: HS
authors.lastname: Park
authors.affiliation: 1] Department of Microbiology, Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: 1] Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, HMR Room 401, 2011 Zonal Avenue, Los Angeles, California 90033, USA [2] Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, HMR Room 401, 2011 Zonal Avenue, Los Angeles, California 90033, USA.
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D000070584:Tripartite Motif Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C550446:TRIM9 protein, human; D044767:Ubiquitin-Protein Ligases