Figure 1

(a) The central role of cIAP1 in NF-κB signalling and programmed cell death. Binding of tumour necrosis factor alpha (TNF-α) to its plasma membrane receptor (TNFR) invokes assembly of TNF-α receptor associated death domain (TRADD), RIP1 kinase (RIP1), TNFR associated factor 2 or 5 (TRAF2/5), and cIAP1 or cIAP2 that together form TNFR Complex I. The E3 ubiquitin ligase activity of cIAP1 can act to buffer high levels of cIAP2 protein through K48-linked polyubiquitylation and degradation of cIAP2. cIAP1 has a critical role in activating the NF-κB pathway through K63-linked polyubiquitylation of RIP1 kinase and/or TRAF2 or 5. The propagation of the NF-κB signal into the nucleus induces expression of a number of pro-survival genes including cIAP2 and inducible nitric oxide synthetase (iNOS). The lack of cIAP1 ubiquitin ligase activity leads to receptor internalisation and the formation of death-inducing cytosolic complexes mediated by deubiquitylated RIP1. Specifically, the RIP1- and RIP3-containing Complex II can form to activate caspase 8, leading to cleavage and inactivation of RIP1 and RIP3 and the initiation of an apoptotic cascade. Alternatively, in the absence of caspase-8 or in a context where deubiquitylated RIP1 or RIP3 activity is high, the ‘necrosome’ (complex III) can form, in which mutual and auto-phosphorylation of RIP1 and RIP3 (labelled ‘P’ in this diagram) leads to propagation of necrotic signals and programmed necrotic cell death. Reactive oxygen species (ROS) are an important mediator of necroptosis and cIAP1 limits RIP1-dependent production of ROS through the mitochondrial electron transport chain. As RIP1 and RIP3 do not translocate to mitochondria in the absence of cIAP1, an unknown factor (labelled ‘X’ in the diagram) must be responsible for increased mitochondrial redox activity. (b) cIAP1 mRNA sequence features and post-transcriptional regulatory nodes. A diagram of the capped (m7G) and polyadenylated cIAP1 mRNA illustrating the size (in kilobases, kb) and location of the 5′ and 3′ untranslated regions (UTRs). This diagram is not to scale. RNA binding proteins have been found to alter cIAP1 mRNA stability and translation. Specifically, ultraviolet radiation induces nucleocytoplasmic translocation of hnRNPA1 and binding to AU-rich elements in the 3′UTR, leading to decreased cIAP1 mRNA stability. An IRES that enhances translation of cIAP1 mRNA following endoplasmic reticulum (ER) stress is 150 bp long and is located proximal to the initiation codon (AUG) of the main open reading frame (ORF). An upstream ORF (uORF) whose CUG initiation codon bisects the IRES codes for a non-functional peptide of 21 amino acids and acts to repress cIAP1 mRNA translation under normal physiological conditions. Several RNA binding proteins or IRES trans-acting factors (ITAFs) have been implicated in the regulation of cIAP1 translation including p86 nuclear factors 90 and 45 (NF90 and NF45, respectively), insulin-like growth factor 2 binding protein 1 (IGF2BP1), and RNA helicase A (RHA)