Journal
SCIENCE SIGNALING
Volume 7, Issue 356, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2005533
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Funding
- Scientific Research of MEXT (Ministry of Education, Culture, Sports, Science and Technology)
- Japan Society for the Promotion of Science
- Takeda Science Foundation
- Naito Foundation
- Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology (PRESTO)
- Grants-in-Aid for Scientific Research [23590577, 21117003, 26293106] Funding Source: KAKEN
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The nuclear PDZ-LIM domain protein PDLIM2 acts as a ubiquitin E3 ligase that targets the p65 subunit of the transcription factor nuclear factor kappa B (NF-kappa B) 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-kappa B 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-kappa B-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-kappa B signaling by acting as a bridge between a ubiquitin E3 ligase and the proteasome.
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