title: HSP70 mediates degradation of the p65 subunit of nuclear factor κB to inhibit inflammatory signaling.
abstract: The nuclear PDZ-LIM domain protein PDLIM2 acts as a ubiquitin E3 ligase that targets the p65 subunit of the transcription factor nuclear factor κB (NF-κB) for degradation, thus preventing excessive inflammatory responses. We found that the chaperone protein HSP70 (heat shock protein of 70 kD) was required for the PDLIM2-mediated degradation of p65 and suppression of NF-κB signaling in lipopolysaccharide (LPS)-treated dendritic cells. In response to LPS, HSP70 translocated to the nucleus where it associated with PDLIM2 and the proteasome-associated protein BAG-1 (BCL2-associated athanogene 1) and promoted the transport of the NF-κB-PDLIM2 complex to the proteasome, thereby facilitating the degradation of p65. Consistent with these data, mouse dendritic cells deficient in either HSP70 or BAG-1 had more nuclear p65 and produced more proinflammatory cytokines than did wild-type dendritic cells. Furthermore, HSP70-deficient mice had more sustained inflammatory responses to bacterial infection than did wild-type mice. These data suggest that in addition to acting as a chaperone during protein folding, HSP70 plays a role in inhibiting proinflammatory NF-κB signaling by acting as a bridge between a ubiquitin E3 ligase and the proteasome.
authors.affiliation: Laboratory for Inflammatory Regulation, RIKEN Center for Integrative Medical Sciences, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan. Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. takashi.tanaka@riken.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Laboratory for Inflammatory Regulation, RIKEN Center for Integrative Medical Sciences, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Shibazaki
authors.affiliation: Laboratory for Inflammatory Regulation, RIKEN Center for Integrative Medical Sciences, RIKEN Research Center for Allergy and Immunology, 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, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan. Laboratory for Immune Regulation, World Premier International Research Center Initiative, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D059748:Proteolysis; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D060588:LIM Domain Proteins; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; C502929:PDLIM2 protein, human; C508508:Pdlim2 protein, mouse; C498143:RELA protein, human; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex