| First Author | Tanaka T | Year | 2014 |
| Journal | Sci Signal | Volume | 7 |
| Issue | 356 | Pages | ra119 |
| PubMed ID | 25515536 | Mgi Jnum | J:258150 |
| Mgi Id | MGI:6142230 | Doi | 10.1126/scisignal.2005533 |
| Citation | Tanaka T, et al. (2014) HSP70 mediates degradation of the p65 subunit of nuclear factor kappaB to inhibit inflammatory signaling. Sci Signal 7(356):ra119 |
| abstractText | The nuclear PDZ-LIM domain protein PDLIM2 acts as a ubiquitin E3 ligase that targets the p65 subunit of the transcription factor nuclear factor kappaB (NF-kappaB) 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-kappaB 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-kappaB-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-kappaB signaling by acting as a bridge between a ubiquitin E3 ligase and the proteasome. |
