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-kappa B transcription factor is key to control inflammation. I kappa B alpha maintains NF-kappa B in an inactive form in the cytoplasm of unstimulated cells, whereas nuclear NF-kappa B in activated cells is degraded by PDLIM2, a nuclear ubiquitin E3 ligase that belongs to a LIM protein family. How NF-kappa B activation is negatively controlled, however, is not completely understood. Here we show that PDLIM1, another member of LIM proteins, negatively regulates NF-kappa B-mediated signaling in the cytoplasm. PDLIM1 sequestered p65 subunit of NF-kappa B in the cytoplasm and suppressed its nuclear translocation in an I kappa B alpha-independent, but alpha-actinin-4-dependent manner. Consistently, PDLIM1 deficiency lead to increased levels of nuclear p65 protein, and thus enhanced proinflammatory cytokine production in response to innate stimuli. These studies reveal an essential role of PDLIM1 in suppressing NF-kappa B activation and suggest that LIM proteins comprise a new family of negative regulators of NF-kappa B signaling through different mechanisms.