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

Rumiko Ono; Tsuneyasu Kaisho; Takashi Tanaka

doi:10.1038/srep18327

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

Sci Rep. 2015 Dec 18:5:18327. doi: 10.1038/srep18327.

Authors

Rumiko Ono^{1

2}, Tsuneyasu Kaisho^{1

3}, Takashi Tanaka^{1

4}

Affiliations

¹ Laboratory for Inflammatory Regulation, RIKEN Center for Integrative Medical Sciences (IMS), RIKEN Research Center for Allergy and Immunology (RCAI), Yokohama, Kanagawa 230-0045, Japan.
² Division of Immunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan.
³ Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.
⁴ Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.

Abstract

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. Here we show that PDLIM1, another member of LIM proteins, negatively regulates NF-κB-mediated signaling in the cytoplasm. PDLIM1 sequestered p65 subunit of NF-κB in the cytoplasm and suppressed its nuclear translocation in an IκBα-independent, but α-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-κB activation and suggest that LIM proteins comprise a new family of negative regulators of NF-κB signaling through different mechanisms.

Publication types

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

MeSH terms

Actinin / metabolism
Animals
Cell Line
Cell Nucleus / metabolism
Cytokines / metabolism
Cytoplasm / metabolism
Dendritic Cells / cytology
Dendritic Cells / metabolism
HEK293 Cells
Humans
I-kappa B Proteins / antagonists & inhibitors
I-kappa B Proteins / genetics
I-kappa B Proteins / metabolism
LIM Domain Proteins / chemistry
LIM Domain Proteins / genetics
LIM Domain Proteins / metabolism*
Lipopolysaccharides / toxicity
Mice
Mice, Knockout
Microfilament Proteins / metabolism
NF-KappaB Inhibitor alpha
NF-kappa B / metabolism
NIH 3T3 Cells
Protein Binding
RNA Interference
Signal Transduction* / drug effects
Transcription Factor RelA / chemistry
Transcription Factor RelA / metabolism*
Transcription Factors / chemistry
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

Cytokines
I-kappa B Proteins
LIM Domain Proteins
Ldb2 protein, mouse
Lipopolysaccharides
Microfilament Proteins
NF-kappa B
Pdlim4 protein, mouse
Transcription Factor RelA
Transcription Factors
Actinin
NF-KappaB Inhibitor alpha