Review
IAPs, regulators of innate immunity and inflammation

https://doi.org/10.1016/j.semcdb.2014.03.035Get rights and content

Highlights

  • The role of IAPs extends apoptosis inhibition.

  • XIAP, cIAP1 and cIAP2 regulate innate immune responses downstream of various PRRs and TNFRs.

  • IAPs regulate inflammatory responses through their E3 ubiquitin ligase activities.

  • cIAP1/2 regulate both the canonical and the non-canonical NF-κB pathways.

  • IAPs are inhibitors of necroptosis, or programmed necrosis.

Abstract

As indicated by their name, members of the Inhibitor of APoptosis (IAP) family were first believed to be functionally restricted to apoptosis inhibition. It is now clear that IAPs have a much wider spectrum of action, and recent studies even suggest that some of its members primarily regulate inflammatory responses. Inflammation, the first response of the immune system to infection or tissue injury, is highly regulated by ubiquitylation – a posttranslational modification of proteins with various consequences. In this review, we focus on the recently reported functions of XIAP, cIAP1 and cIAP2 as ubiquitin ligases regulating innate immunity and inflammation.

Introduction

The first member of the Inhibitor of APoptosis (IAP) family was identified 20 years ago as a baculovirus protein contributing to efficient viral replication by sustaining survival of the infected insect host cell [1]. Since then, IAP orthologs have been identified in various organisms, and the human genome was shown to encode eight of them (BIRC1/NAIP, BIRC2/cIAP1, BIRC3/cIAP2, BIRC4/XIAP, BIRC5/Survivin, BIRC6/BRUCE, BIRC7/ML-IAP and BIRC8/ILP2) [2], [3]. The defining feature of IAPs is the presence of at least one baculovirus IAP repeat (BIR) domain, a protein-protein interaction motif that is required for the anti-apoptotic potential of some IAP family members [4], [5], [6]. Another important characteristic of certain IAPs, such as mammalian XIAP, cIAP1 and cIAP2 (cIAP1/2), is the presence of a C-terminal RING domain conferring upon them ubiquitin (Ub)-ligase activity.

Protein ubiquitylation, the covalent attachment of Ub – a 76-amino acid polypeptide – to a target protein, has crucial roles in the regulation of many physiological processes, such as protein degradation, signal transduction, or even protein trafficking. It is a dynamic process that is catalyzed by the concerted action of a Ub-activating enzyme (E1), a Ub-conjugating enzyme (E2) and a Ub-ligase (E3), and which is negatively regulated by de-ubiquitylases (DUBs) [7] (Fig. 1). The wide range of consequences of protein ubiquitylation originates from the fact that this process can result in the conjugation of either one Ub molecule (mono-ubiquitylation) or various Ub chains (poly-ubiquitylation) to the substrate. Ubiquitin polymers are generated out of eight possible Ub–Ub linkages. Importantly, each Ub linkage has a different topology, which allows specificity in their recognition by the different Ub binding domain (UBD)-containing proteins that function as Ub receptors [8].

Consequently, the type of Ub-linkage will determine the consequence of ubiquitylation. It is for example well established that K48-linkages are implicated in proteasomal degradation while K63-and linear-linkages serve as docking sites promoting signal transduction.

As indicated by their name, IAPs were first believed to be functionally restricted to inhibition of apoptosis, mostly by direct interference, via their BIR domains, with the proteolytic activity of caspases [9]. Several later studies however demonstrated that not all IAPs protect cells from apoptotic stimuli, and that amongst the mammalian IAPs, XIAP is probably the only family member capable of direct caspase inhibition [10], [11]. Other pro-survival IAPs, such as cIAP1 and cIAP2, bind to the effector caspase-7 and -3, but are inefficient in physically interfering with their proteolytic activities. Instead, these IAPs were suggested to neutralize caspase-7 and -3 by conjugating them with K48-Ub chains that promote their proteasomal degradation [12]. Of note, the pro-survival function of cIAP1/2 is not limited to caspase regulation but also involves their ability to activate, in an E3-dependent manner, the canonical Nuclear Factor-κB (NF-κB) pathway, which drives expression of various pro-survival molecules [13], [14], [15], [16]. In addition, cIAP1/2 protect cells from death by regulating Receptor Interacting Protein Kinase (RIPK)-1 and -3 activities [17], [18].

It is now clear that IAPs have a much broader spectrum of action than promoting cell survival by caspase regulation [4], [19]. Recent findings may even suggest that the primary function of some IAPs consist in the regulation of inflammatory and innate immune signaling pathways, a function attributed to their E3 Ub-ligase activities [4], [20], [21], [22], [23], [24], [25], [26], [27], [28]. In this review, we focus on the recently reported roles of XIAP, cIAP1 and cIAP2 as Ub-ligases regulating innate immunity and inflammation.

Section snippets

IAPs are major regulators of inflammatory responses

Inflammation, the first response of the immune system to infection or tissue injury, is initiated by the sensing of “stress” signals by members of the innate immune Pattern-Recognition Receptors (PRRs) superfamily. These receptors detect the presence of conserved microbial components, called Pathogen-Associated Molecular Patterns (PAMPs), and/or endogenous intracellular molecules, called Danger/Damage-Associated Molecular Patterns (DAMPs), that are released by dying cells [29]. Upon binding of

Conclusion and future perspectives

Although best known for their ability to suppress cell death through caspase inhibition, recent studies have highlighted the critical role of cIAP1, cIAP2 and XIAP as major regulators of inflammation. This newly revealed function was shown to entirely rely on their Ub-ligase activity, which allows them not only to regulate NFκB, MAPK or IRF pathways downstream of various PRRs and TNFRs but also to control inflammasome activation. Knowing the importance of inflammation in the development of many

Acknowledgements

M.B. has a tenure track position within the Multidisciplinary Research Program of Ghent University (GROUP-ID). Research in his unit, headed by Prof. Vandenabeele, is supported by a Methusalem grant (BOF09/01M00709), European grants (Euregional PACT II), Belgian grants (Interuniversity Attraction Poles, IAP 7/32), Flemish grants (Research Foundation Flanders, FWO G.0875.11, FWO G.0973.11, FWO G.0A45.12N, FWO G.0172.12N, FWO G0787.13N), Ghent University grants (MRP, GROUP-ID consortium) and

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