PDLIM1 inhibits NF-κB-mediated inflammatory signaling by sequestering the p65 subunit of NF-κB in the cytoplasm.

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.

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

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.