Article
- The EMBO Journal (1997) 16, 6486 - 6494
- doi:10.1093/emboj/16.21.6486
Inhibition of NF-
B cellular function via specific targeting of the IB-ubiquitin ligase
Avraham Yaron1, Hedva Gonen2, Irit Alkalay1, Ada Hatzubai1, Steffen Jung1, Shaul Beyth3, Frank Mercurio4, Anthony M. Manning4, Aaron Ciechanover2 and Yinon Ben-Neriah1
- The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel
- Department of Biochemistry and the Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel
- Department of Cellular Biochemistry, The Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel
- Signal Pharmaceuticals Inc., San Diego, CA 92121, USA
Correspondence to:
Aaron Ciechanover, E-mail: mdaaron@techunix.technion.ac.il
Yinon Ben-Neriah, E-mail: yinon@cc.huji.ac.il
Received 24 May 1997; Revised 13 August 1997
Abstract
Activation of the transcription factor NF-
B is a paradigm for signal transduction through the ubiquitin–proteasome pathway: ubiquitin-dependent degradation of the transcriptional inhibitor IB in response to cell stimulation. A major issue in this context is the nature of the recognition signal and the targeting enzyme involved in the proteolytic process. Here we show that following a stimulus-dependent phosphorylation, and while associated with NF-B, IB is targeted by a specific ubiquitin-ligase via direct recognition of the signal-dependent phosphorylation site; phosphopeptides corresponding to this site specifically inhibit ubiquitin conjugation of IB and its subsequent degradation. The ligase recognition signal is functionally conserved between IB
and IB
, and does not involve the nearby ubiquitination site. Microinjection of the inhibitory peptides into stimulated cells abolished NF-B activation in response to TNF and the consequent expression of E-selectin, an NF-B-dependent cell-adhesion molecule. Inhibition of NF-B function by specific blocking of ubiquitin ligase activity provides a novel approach for intervening in cellular processes via regulation of unique proteolytic events.
Keywords:
- degradation,
- IB phosphorylation,
- NF-B,
- ubiquitin,
- ubiquitin ligase motif
