Two distinct signalling cascades target the NF-kappaB regulatory factor c-IAP1 for degradation.
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.
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- Ubiquitination
- TNF Receptor-Associated Factor 2
- Signal Transduction
- Protein Transport
- NF-kappa B
- Multiprotein Complexes
- Ki-1 Antigen
- Inhibitor of Apoptosis Proteins
- Humans
- Cytoplasm
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Ubiquitination
- TNF Receptor-Associated Factor 2
- Signal Transduction
- Protein Transport
- NF-kappa B
- Multiprotein Complexes
- Ki-1 Antigen
- Inhibitor of Apoptosis Proteins
- Humans
- Cytoplasm