Two distinct signalling cascades target the NF-kappaB regulatory factor c-IAP1 for degradation.

Abstract

c-IAP1 (cellular inhibitor of apoptosis 1) has recently emerged as a negative regulator of the non-canonical NF-kappaB (nuclear factor kappaB) signalling cascade. Whereas synthetic IAP inhibitors have been shown to trigger the autoubiquitination and degradation of c-IAP1, less is known about the physiological mechanisms by which c-IAP1 stability is regulated. In the present paper, we describe two distinct cellular processes that lead to the targeted loss of c-IAP1. Recruitment of a TRAF2 (tumour necrosis factor receptor-associated factor 2)-c-IAP1 complex to the cytoplasmic domain of the Hodgkin's/anaplastic large-cell lymphoma-associated receptor, CD30, leads to the targeting and degradation of the TRAF2-c-IAP1 heterodimer through a mechanism requiring the RING (really interesting new gene) domain of TRAF2, but not c-IAP1. In contrast, the induced autoubiquitination of c-IAP1 by IAP antagonists causes the selective loss of c-IAP1, but not TRAF2, thereby releasing TRAF2. Thus c-IAP1 can be targeted for degradation by two distinct processes, revealing the critical importance of this molecule as a regulator of numerous intracellular signalling cascades.

• Authors: Rebecca A Csomos, Casey W Wright, Stefanie Galbán, Karolyn A Oetjen, Colin S Duckett
• Journal: The Biochemical journal (Biochem J) Vol. 420 Issue 1 Pg. 83-91 (Apr 28 2009) ISSN: 1470-8728 [Electronic] England
• PMID: 19243308 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Inhibitor of Apoptosis Proteins
• Ki-1 Antigen
• Multiprotein Complexes
• NF-kappa B
• TNF Receptor-Associated Factor 2

Topics

• Cell Line
• Cytoplasm
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Ki-1 Antigen (metabolism)
• Multiprotein Complexes (metabolism)
• NF-kappa B (metabolism)
• Protein Transport
• Signal Transduction
• TNF Receptor-Associated Factor 2 (metabolism)
• Ubiquitination