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  • Review Article
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The role of the IAP E3 ubiquitin ligases in regulating pattern-recognition receptor signalling

Nature Reviews Immunology volume 12, pages 833–844 (2012)Cite this article

Subjects

Key Points

  • It is now clear that the functions of inhibitor of apoptosis proteins (IAPs) are not restricted to the inhibition of apoptosis. Some family members, such as X-linked IAP (XIAP), cellular IAP1 (cIAP1) and cIAP2, have emerged as crucial regulators of the host innate immune responses to infection or injury in part by regulating the signalling pathways activated downstream of several pattern-recognition receptors (PRRs).

  • XIAP, cIAP1 and cIAP2 positively regulate induction of pro-inflammatory cytokines downstream of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and NOD2, Toll-like receptor 2 (TLR2) and TLR4, and retinoic acid-inducible gene I (RIG-I). Importantly, the function of the fly orthologue DIAP2 in the IMD pathway shows that the role of IAPs in the regulation of PRR signalling is phylogenetically and functionally conserved.

  • IAPs regulate PRR signalling through their E3 ubiquitin ligase activities.

  • The roles of cIAP1 and cIAP2 in NOD1, NOD2 and RIG-I signalling pathways seem to be non-redundant, as a single IAP deletion is sufficient to repress innate immune responses downstream of these PRRs.

  • XIAP, cIAP1 and cIAP2 have also been reported to regulate inflammasome activation and interleukin-1β secretion. However, further studies are required to clearly establish whether they positively or negatively regulate these processes.

  • Small-molecule IAP antagonists, termed SMAC mimetics, inhibit cIAP1, cIAP2 and XIAP and therefore represent attractive tools for the treatment of inflammatory diseases mediated by IAP-dependent PRR signalling.

Abstract

An inflammatory response is initiated when innate immune pattern-recognition receptors (PRRs) expressed by different cell types detect constituents of invading microorganisms and endogenous intracellular molecules released by dying cells. The intracellular cascades activated by PRRs induce the expression and maturation of inflammatory molecules that coordinate the removal of the infectious agents and of the infected or damaged cells. In this Review, we discuss the findings implicating members of the inhibitor of apoptosis protein (IAP) family in the ubiquitylation-dependent regulation of PRR signalling. Understanding the role of IAPs in innate immunity may open new therapeutic perspectives for the treatment of PRR-dependent inflammatory diseases.

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Figure 1: Ubiquitylation system.
Figure 2: IAPs in the regulation of the innate immune response.
Figure 3: Model of DIAP2-dependent regulation of the IMD pathway.
Figure 4: Model of IAP-dependent regulation of NOD1 and NOD2 immunity.
Figure 5: Model of cIAP1- and cIAP2-dependent regulation of the TLR4–MYD88 pathway.
Figure 6: cIAP1 and cIAP2 in the regulation of RIG-I-mediated antiviral response.
Figure 7: The apparently discrepant roles of IAPs in inflammasome regulation.

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Acknowledgements

M.J.M.B. has a tenure track position in the Multidisciplinary Research Program of Ghent University (GROUP-ID). Research in his group is supported by grants from The Research Foundation – Flanders (FWO G.0172.12N), the Interuniversity Attraction Poles programme (IAP 7), the Methusalem programme of the Flemish government (BOF09/01M00709) and the Flanders Institute for Biotechnology (VIB). P.V. is full professor at Ghent University and senior principal investigator at the VIB. Research in the Vandenabeele group is supported by European grants (Euregional PACT II), Belgian grants (IAP 7), Flemish grants (FWO G.0875.11, FWO G.0973.11 and FWO G.0A45.12N), a Ghent University grant (GROUP-ID) and grants from the VIB. P.V. also holds a Methusalem grant (BOF09/01M00709).

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  1. Department for Molecular Biomedical Research, VIB, Ghent, B-9052, Belgium

    Peter Vandenabeele & Mathieu J. M. Bertrand

  2. Department of Biomedical Molecular Biology, Ghent University, Ghent, B-9052, Belgium

    Peter Vandenabeele & Mathieu J. M. Bertrand

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  1. Peter Vandenabeele
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Correspondence to Peter Vandenabeele or Mathieu J. M. Bertrand.

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Glossary

OMI

(Also known as HTRA2). An endogenous inhibitor of apoptosis protein (IAP) antagonist released from the intermembrane space of the mitochondria during apoptosis. It binds to X-linked IAP (XIAP), cellular IAP1 (cIAP1) and cIAP2 via an N-terminal tetrapeptide IAP-binding motif (IBM) and induces the proteolytic inactivation of IAPs, as well as of receptor interacting protein kinase 1 (RIPK1), leading to increased caspase activation.

SMAC

(Second mitochondria-derived activator of caspase; also known as DIABLO). An endogenous inhibitor of apoptosis protein (IAP) antagonist released from the intermembrane mitochondrial space following a wide range of death stimuli. Its cleavage releases an N-terminal tetrapeptide IAP-binding motif (IBM), allowing it to bind and inhibit X-linked IAP (XIAP), cellular IAP1 (cIAP1) and cIAP2, causing an increase in the activation of caspases.

Receptor interacting protein kinase 1

(RIPK1). A serine/threonine protein kinase from the RIPK family that is involved in a variety of cellular pathways downstream of tumour necrosis factor receptor family members and pattern-recognition receptors. RIPK1 has kinase-independent functions in the nuclear factor-κB and mitogen-activated protein kinase pathways, but has kinase-dependent functions in apoptotic and necroptotic cell death pathways.

SMAC mimetic

(Second mitochondria-derived activator of caspase mimetic). A synthetic inhibitor of apoptosis protein (IAP) antagonist that mimics the structural characteristics of the tetrapeptide IAP-binding motif (IBM) of SMAC, which is revealed following proteolytic cleavage of SMAC. These compounds inhibit X-linked IAP (XIAP) function but also induce proteasomal degradation of cellular IAP1 (cIAP1) and cIAP2.

TRAF proteins

A family of conserved proteins that link receptors of the tumour necrosis factor, interleukin-1 and Toll-like receptor families to downstream signalling pathways, such as activation of the transcription factors nuclear factor-κB (via IκB kinases) and activator protein 1 (via mitogen-activated protein kinases).

Linear ubiquitylation

The conjugation of a linear ubiquitin chain — generated by attachment of the C-terminal glycine residue of one ubiquitin to the N-terminal methionine residue of another ubiquitin — to a lysine residue of a specific substrate. Linear ubiquitin chain assembly complex (LUBAC) is an E3 complex that specifically generates linear ubiquitin chains.

Necroptosis

A regulated form of necrosis that depends on receptor interacting protein kinase 1 (RIPK1) and RIPK3 kinase activity. It is characterized by rounding of the cells (oncosis), plasma membrane rupture and cytoplasmic leakage, and by the absence of apoptotic markers such as caspase activation, membrane blebbing, nuclear shrinkage and chromatin condensation (pyknosis), nuclear fragmentation (karyorrhexis) and internucleosomal DNA cleavage.

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Vandenabeele, P., Bertrand, M. The role of the IAP E3 ubiquitin ligases in regulating pattern-recognition receptor signalling. Nat Rev Immunol 12, 833–844 (2012). https://doi.org/10.1038/nri3325

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