Article
- The EMBO Journal (2009) 28, 513 - 522
- doi:10.1038/emboj.2008.285
Published online: 8 January 2009
There is a Have you seen ...? (March 2009) associated with this Article.
Subject Categories:
The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-
B signalling
Noula Shembade1, Kislay Parvatiyar1, Nicole S Harhaj1 and Edward W Harhaj1
- Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, FL, USA
Correspondence to:
Edward W Harhaj, Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, 1550 NW 10 Avenue, Miami, FL 33136, USA. Tel.: +1 305 243 7893; Fax: +1 305 243 6410; E-mail: eharhaj@med.miami.edu
Received 10 July 2008; Accepted 8 December 2008
Abstract
The RING domain protein RNF11 is overexpressed in breast cancers and promotes tumour growth factor-beta (TGF-
) signalling. RNF11 has been proposed to regulate TGF- signalling by interacting with HECT- and SCF-type E3 ligases; however, the role of RNF11 in other signalling pathways is poorly understood. Here, we demonstrate a novel function of RNF11 as a negative regulator of NF-
B and jun N-terminal kinase (JNK) signalling pathways. Knockdown of RNF11 with siRNA resulted in persistent tumour necrosis factor (TNF)- and lipopolysaccharide (LPS)-mediated NF-B and JNK signalling. RNF11 interacted with the NF-B inhibitor A20 and its regulatory protein TAX1BP1 in a stimulus-dependent manner. RNF11 negatively regulated RIP1 and TRAF6 ubiquitination upon stimulation with TNF and LPS, respectively. Furthermore, RNF11 was required for A20 to interact with and inactivate RIP1 to inhibit TNF-mediated NF-B activation. Our studies reveal that RNF11, together with TAX1BP1 and Itch, is an essential component of an A20 ubiquitin-editing protein complex that ensures transient activation of inflammatory signalling pathways.
Keywords:
- A20,
- Itch,
- NF-B,
- RNF11,
- TAX1BP1
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