HSP70 mediates degradation of the p65 subunit of nuclear factor κB to inhibit inflammatory signaling

Takashi Tanaka; Azusa Shibazaki; Rumiko Ono; Tsuneyasu Kaisho

doi:10.1126/scisignal.2005533

HSP70 mediates degradation of the p65 subunit of nuclear factor κB to inhibit inflammatory signaling

Sci Signal. 2014 Dec 16;7(356):ra119. doi: 10.1126/scisignal.2005533.

Authors

Takashi Tanaka¹, Azusa Shibazaki², Rumiko Ono², Tsuneyasu Kaisho³

Affiliations

¹ 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.
² Laboratory for Inflammatory Regulation, RIKEN Center for Integrative Medical Sciences, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
³ 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.

PMID: 25515536
DOI: 10.1126/scisignal.2005533

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Dendritic Cells / metabolism*
Dendritic Cells / pathology
HEK293 Cells
HSP70 Heat-Shock Proteins / genetics
HSP70 Heat-Shock Proteins / metabolism*
Humans
Inflammation / chemically induced
Inflammation / genetics
Inflammation / metabolism
LIM Domain Proteins / genetics
LIM Domain Proteins / metabolism
Lipopolysaccharides / toxicity
Mice
Microfilament Proteins / genetics
Microfilament Proteins / metabolism
Proteasome Endopeptidase Complex / genetics
Proteasome Endopeptidase Complex / metabolism
Protein Folding
Proteolysis*
Signal Transduction*
Transcription Factor RelA / genetics
Transcription Factor RelA / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism

Substances

Adaptor Proteins, Signal Transducing
BCL2-associated athanogene 1 protein
DNA-Binding Proteins
HSP70 Heat-Shock Proteins
LIM Domain Proteins
Lipopolysaccharides
Microfilament Proteins
PDLIM2 protein, human
Pdlim2 protein, mouse
RELA protein, human
Rela protein, mouse
Transcription Factor RelA
Transcription Factors
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex