title: PDLIM1 inhibits NF-κB-mediated inflammatory signaling by sequestering the p65 subunit of NF-κB in the cytoplasm.
abstract: Understanding the regulatory mechanisms for the NF-κB transcription factor is key to control inflammation. IκBα maintains NF-κB in an inactive form in the cytoplasm of unstimulated cells, whereas nuclear NF-κB in activated cells is degraded by PDLIM2, a nuclear ubiquitin E3 ligase that belongs to a LIM protein family. How NF-κB activation is negatively controlled, however, is not completely understood. Here we show that PDLIM1, another member of LIM proteins, negatively regulates NF-κB-mediated signaling in the cytoplasm. PDLIM1 sequestered p65 subunit of NF-κB in the cytoplasm and suppressed its nuclear translocation in an IκBα-independent, but α-actinin-4-dependent manner. Consistently, PDLIM1 deficiency lead to increased levels of nuclear p65 protein, and thus enhanced proinflammatory cytokine production in response to innate stimuli. These studies reveal an essential role of PDLIM1 in suppressing NF-κB activation and suggest that LIM proteins comprise a new family of negative regulators of NF-κB signaling through different mechanisms.
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.|Division of Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Rumiko
authors.initials: R
authors.lastname: Ono
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.|Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
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.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000185:Actinin / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D060588:LIM Domain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D060588:LIM Domain Proteins; C106649:Ldb2 protein, mouse; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D016328:NF-kappa B; C486248:Pdlim4 protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000185:Actinin; D000072000:NF-KappaB Inhibitor alpha