DOI:10.1038/nri2104 The transcription factor NF-κB

(nuclear factor-κB) is an important regulator of inflammatory responses. However, NF-κB activation must be terminated in a timely manner as excessive inflammation can cause tissue damage and disease. Now, Takashi Tanaka and colleagues report a new way of terminating NF-κB activation: PDLIM2 (a nuclear pro-tein containing a PDZ domain and a LIM domain) acts as an E3 ubiquitin ligase, promoting ubiquitylation of the p65 subunit of NF-κB and leading to nuclear degradation of p65.

Prior to activation, NF-κB com-ponents are retained in the cytoplasm in an inactive complex in associa-tion with inhibitor of NF-κB (IκB) proteins. Following activation, IκB is ubiquitylated and degraded, allowing the p50 and p65 subunits of NF-κB to translocate to the nucleus and induce expression of pro-inflammatory genes such as those encoding the cytokines interleukin-6 (IL-6) and IL-12. IκBα is transcribed in an NF-κB-dependent manner, and this mediates the export of NF-κB back into the cytoplasm again, thereby terminating the NF-κB response. However, NF-κB activation can be terminated in the absence of IκBα, so other mechanisms must exist. Ubiquitylation and proteasomal degradation of p65 has been proposed as an alternative termination mecha-nism, and the authors sought to identify a ubiquitin ligase that might be responsible for this.

Polyubiquitylation of p65 was detected in the nucleus of mouse embryonic fibroblasts stimulated with lipopolysaccharide (which activates

cells through Toll-like receptors (TLRs)). As PDLIM2 is known to interact with STAT (signal transducer and activator of transcription) mole-cules in the nucleus and promote their degradation, and as it is expressed in macrophages, dendritic cells and T cells, the authors assessed whether it might also act on p65. PDLIM2 co-precipitated with endogenous p65 and when its effect was assessed in a reporter assay, PDLIM2 suppressed p65-dependent luciferase activity in a dose-dependent manner. Using mutants of PDLIM2 lacking either the LIM domain or the PDZ domain, the authors showed that the LIM domain was essential for polyubiquitylation of p65 molecules. Visualization experi-ments indicated that PDLIM2 medi-ates intranuclear trafficking of p65 to insoluble nuclear structures where it

is then degraded by the proteasome. Finally, the authors investigated TLR-induced inflammatory responses in Pdlim2–/– mice and observed a twofold to fourfold increase in the produc-tion of IL-6 and IL-12 in response to lipopolysaccharide in these mice compared with wild-type mice.

This study shows that nuclear degradation mediated by PDLIM2 is an important mechanism for ter-minating NF-κB responses. Further work will be required to determine how PDLIM2 activity itself is regulated.

Elaine Bell

ORIGINAL RESEARCH PAPER Tanaka, T. et al. PDLIM2-mediated termination of transcription factor NF-κB activation by intranuclear sequestration and degradation of the p65 subunit. Nature Immunol. 29 April 2007 (doi:10.1038/ni1464)

I M M U N E R E G U L AT I O N

Terminating inflammatory responses

R E S E A R C H H I G H L I G H T S

NATURE REVIEWS | IMMUNOLOGY VOLUME 7 | JUNE 2007

© 2007 Nature Publishing Group