Inhibitor of Apoptosis (IAP) and BIR‐containing Proteins

Abstract

The inhibitor of apoptosis (IAP) family of proteins are characterized by presence of one or more baculoviral IAP Repeat (BIR) domains, so they are also termed BIRCs, for ‘BIR‐containing’ proteins. The first IAPs were identified in insect‐attacking viruses, which use them to inhibit defensive apoptosis of the host cell. Subsequently, other BIR‐containing proteins have been found in organisms from yeasts to mammals. The human IAP XIAP can block apoptosis by directly inhibiting caspases, whereas cIAP1 and cIAP2 inhibit apoptosis by reducing caspase‐activating signals from tumour necrosis factor (TNF) receptor superfamily members. As the genes for some IAPs are amplified in cancers, they appear to be able to act as oncogenes. IAP‐antagonist compounds modelled on the IAP antagonist Smac/Diablo are being developed for the treatment of cancer, and are currently undergoing clinical trials.

Key concepts

  • All IAPs bear at least one BIR domain, but not all BIR‐containing proteins are inhibitors of apoptosis.

  • XIAP can block apoptosis by directly inhibiting caspases, but cIAP1 and cIAP2 inhibit apoptosis by reducing caspase‐activating signals from TNF receptor superfamily members, and by promoting activation of canonical NFκB pathways rather than noncanonical NFκB pathways.

  • Genes for some IAPs are amplified in cancers, and IAP‐antagonist compounds modelled on the IAP antagonist Smac/Diablo are being developed for the treatment of cancer.

  • Survivin and BRUCE are not apoptosis inhibitors, but are needed for cell division.

Keywords: XIAP; cIAP1; cIAP2; IAP; Survivin; BIR

Figure 1.

The defining characteristic of all IAPs is the presence of one or more baculoviral IAP repeats (BIRs; red ovals). BIRs allow binding to a variety of other proteins, such as caspases and IAP antagonists (e.g. BIR2 and BIR3 of cIAPs and XIAP). cIAP1&2 bind to TRAF2 via their BIR1 domains. Many IAPs bear C‐terminal RING domains (blue rectangles) that allow them to act as ubiquitin E3 ligases. After dimerization, the RINGs associate with E2s. Several of the IAPs bear UBA domains, which act as receptors for K63‐linked poly ubiquitinylated proteins. In addition to BIRs and an NTPase domain, NAIP bears leucine‐rich repeats, which are often found in proteins involved in innate immunity. The single BIRs in Survivin and BRUCE resemble each other more than the BIRs of other BIRCs, and both these proteins act mainly during mitosis to allow proper chromosome segregation.

Figure 2.

Complex of Smac/DIABLO dimer with BIR3s from XIAP. The BIRs are shown in blue; note the zinc ions. The residues (AVPI …) at the processed amino‐terminus of smac/DIABLO (red) bind into a groove of the surface of the BIRs. Synthetic IAP antagonist compounds have been designed that mimic the N‐terminus of smac/DIABLO, and are therefore sometimes termed ‘smac‐mimetics’. The remainder of smac/DIABLO is composed of extended α helices (purple). (This figure is based on the structure produced by (Wu et al., ).

Figure 3.

Roles for cIAP1 in TNF signaling. In unstimulated cells (left), cIAP1 (together with TRAF2 & TRAF3) ubiquitylate NIK, preventing it from accumulating, so that activation of noncanonical NFκB p100 is suppressed. When TNF is added to cells (right), a complex forms on the cytoplasmic domains of TNFR1. RIP1, TRAF2 and cIAP1 interact, causing K63‐ubiquitylation of NEMO, which activates canonical NFκB, as well as generating signals that activate MAP‐kinases. These pathways can lead to induction of antiapoptotic proteins such as A20, FLIP, A1 and cIAP2, that are usually sufficient to prevent death of the cell from apoptosis caused by aggregation of FADD and activation of caspase 8 (far right). However, in cells treated with IAP antagonist compounds, cIAP1 autoubiquitylates and is degraded. This leads to increased levels of NIK, and processing of p100 NFκB2 to p52, but reduced antiapoptotic signalling by the TNF receptors. Cells treated with IAP antagonists, or with NFκB inhibitors, therefore readily activate FADD and caspase 8 and undergo apoptosis when exposed to TNF.

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Vaux, David L(Sep 2009) Inhibitor of Apoptosis (IAP) and BIR‐containing Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021570]