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  • The EMBO Journal (2007) 26, 1532 - 1541
  • doi:10.1038/sj.emboj.7601600

Published online: 22 February 2007

CSN controls NF-kappaB by deubiquitinylation of IkappaBalpha

Katrin Schweitzer1, Przemyslaw M Bozko1, Wolfgang Dubiel2 and Michael Naumann1

  1. Medical Faculty, Institute of Experimental Internal Medicine, Otto-von-Guericke-University, Magdeburg, Germany
  2. Division of Molecular Biology, Department of Surgery, Charite, University Medicine, Berlin, Germany

Correspondence to:

Michael Naumann, Medical Faculty, Institute of Experimental Internal Medicine, Otto-von-Guericke-University, Leipziger Strasse 44, 39120 Magdeburg, Germany. Tel.: +49 391 67 13227; Fax: +49 391 67 13312; E-mail: Naumann@medizin.uni-magdeburg.de

Received 19 July 2006; Accepted 18 January 2007

The COP9 signalosome (CSN) is a conserved protein complex that regulates assembly and activity of cullin-RING ubiquitin ligases (CRLs). Ubiquitin-dependent degradation of the NF-kappaB inhibitor IkappaBalpha preceeds nuclear translocation of NF-kappaB. For the first time, we show here an inducible interaction of the CSN with IkappaBalpha and that the CSN controls IkappaBalpha and NF-kappaB activity. Strikingly, disruption of the CSN by a small interfering RNA-mediated knockdown of single CSN subunits results in a reduced re-accumulation of IkappaBalpha and prolonged nuclear translocation of NF-kappaB in TNFalpha-stimulated cells. The control of IkappaBalpha by the CSN is regulated by deubiquitinylation of IkappaBalpha conferred by the CSN-associated deubiquitinylase USP15. Protein expression levels of cullin1 and the CRL substrate adapter beta-TrCP are reduced in nonstimulated cells with a disrupted function of the CSN, which might account for an impaired basal turnover of IkappaBalpha. We propose that the CSN controls both CRL activity and stability of the CRL substrate IkappaBalpha. In consequence, basal and signal-induced CRL-dependent turnover of IkappaBalpha is precisely adapted to specific cellular needs.

  • Keywords:

    • COP9 signalosome,
    • cullin-RING ubiquitin-ligase,
    • Nedd8,
    • ubiquitin,
    • USP15