PDLIM2-mediated termination of transcription factor NF-κB activation by intranuclear sequestration and degradation of the p65 subunit

被引:251
作者
Tanaka, Takashi
Grusby, Michael J.
Kaisho, Tsuneyasu [1 ]
机构
[1] RIKEN, Res Ctr Allergy & Immunol, Host Def Lab, Yokohama, Kanagawa 2300045, Japan
[2] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA
关键词
D O I
10.1038/ni1464
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Activation of transcription factor NF-kappa B in the innate immune system is tightly regulated to prevent excessive inflammatory responses. How NF-kappa B activation is terminated, however, is not fully understood. Here we report that PDLIM2 negatively regulated NF-kappa B activity, acting as a nuclear ubiquitin E3 ligase targeting the p65 subunit of NF-kappa B. PDLIM2 bound to p65 and promoted p65 polyubiquitination. In addition, PDLIM2 targeted p65 to discrete intranuclear compartments where polyubiquitinated p65 was degraded by the proteasome. PDLIM2 deficiency resulted in larger amounts of nuclear p65, defective p65 ubiquitination and augmented production of proinflammatory cytokines in response to innate stimuli. Our findings delineate a pathway by which PDLIM2 terminates NF-kappa B activation through intranuclear sequestration and subsequent degradation.
引用
收藏
页码:584 / 591
页数:8
相关论文
共 46 条
[1]   Intracellular localization of proteasomal degradation of a viral antigen [J].
Antón, LC ;
Schubert, U ;
Bacík, I ;
Princiotta, MF ;
Wearsch, PA ;
Gibbs, J ;
Day, PM ;
Realini, C ;
Rechsteiner, MC ;
Bennink, JR ;
Yewdell, JW .
JOURNAL OF CELL BIOLOGY, 1999, 146 (01) :113-124
[2]  
ARENZANASEISDEDOS F, 1995, MOL CELL BIOL, V15, P2689
[3]  
ArenzanaSeisdedos F, 1997, J CELL SCI, V110, P369
[4]   Opinion - Actin up in the nucleus [J].
Bettinger, BT ;
Gilbert, DM ;
Amberg, DC .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2004, 5 (05) :410-415
[5]   Signaling molecules of the NF-κB pathway shuttle constitutively between cytoplasm and nucleus [J].
Birbach, A ;
Gold, P ;
Binder, BR ;
Hofer, E ;
de Martin, R ;
Schmid, JA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (13) :10842-10851
[6]   Regulation of E2F through ubiquitin-proteasome-dependent degradation: Stabilization by the pRB tumor suppressor protein [J].
Campanero, MR ;
Flemington, EK .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (06) :2221-2226
[7]   Solution structure of the PHD domain from the KAP-1 corepressor: structural determinants for PHD, RING and LIM zinc-binding domains [J].
Capili, AD ;
Schultz, DC ;
Rauscher, FJ ;
Borden, KLB .
EMBO JOURNAL, 2001, 20 (1-2) :165-177
[8]   Recruitment of Topoisomerase I (Scl-70) to Nucleoplasmic Proteasomes in Response to Xenobiotics Suggests a Role for Altered Antigen Processing in Scleroderma [J].
Chen, Min ;
Dittmann, Assemgul ;
Kuhn, Annegret ;
Ruzicka, Thomas ;
von Mikecz, Anna .
ARTHRITIS AND RHEUMATISM, 2005, 52 (03) :877-884
[9]   Gene expression - Emerging roles of ubiquitin in transcription regulation [J].
Conaway, RC ;
Brower, CS ;
Conaway, JW .
SCIENCE, 2002, 296 (5571) :1254-1258
[10]   The ubiquitin ligase COP1 is a critical negative regulator of p53 [J].
Dornan, D ;
Wertz, I ;
Shimizu, H ;
Arnott, D ;
Frantz, GD ;
Dowd, P ;
O' Rourke, K ;
Koeppen, H ;
Dixit, VM .
NATURE, 2004, 429 (6987) :86-92