Recent advances in understanding inhibitor of apoptosis proteins

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

The inhibitor of apoptosis proteins (IAPs) are a family of proteins that were chiefly known for their ability to inhibit apoptosis by blocking caspase activation or activity. Recent research has shown that cellular IAP1 (cIAP1), cIAP2, and X-linked IAP (XIAP) also regulate signaling by receptors of the innate immune system by ubiquitylating their substrates. These IAPs thereby act at the intersection of pathways leading to cell death and inflammation. Mutation of IAP genes can impair tissue homeostasis and is linked to several human diseases. Small-molecule IAP antagonists have been developed to treat certain malignant, infectious, and inflammatory diseases. Here, we will discuss recent advances in our understanding of the functions of cIAP1, cIAP2, and XIAP; the consequences of their mutation or dysregulation; and the therapeutic potential of IAP antagonist drugs.

Related collections

Most cited references 138

Record: found
Abstract: found
Article: not found

Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

J Hugot, M Chamaillard, H Zouali … (2001)

Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

0 comments Cited 911 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

Olivier Micheau, Jurg Tschopp (2003)

Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.

0 comments Cited 719 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL

Kate E. Lawlor, Nufail Khan, Alison Mildenhall … (2015)

RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3–caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1β inflammatory responses independent of MLKL and necroptotic cell death.

0 comments Cited 306 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Najoua Lalaoui: Role: ConceptualizationRole: Funding AcquisitionRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0002-0165-3324

David Lawrence Vaux: Role: Funding AcquisitionRole: Writing – Review & Editing

Journal

Journal ID (nlm-ta): F1000Res

Journal ID (iso-abbrev): F1000Res

Journal ID (pmc): F1000Research

Title: F1000Research

Publisher: F1000 Research Limited (London, UK )

ISSN (Electronic): 2046-1402

Publication date (Electronic): 3 December 2018

Publication date Collection: 2018

Volume: 7

Electronic Location Identifier: F1000 Faculty Rev-1889

Affiliations

[1 ]Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, 3052, Australia

[2 ]Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, 3050, Australia

Author notes

[a ] lalaoui@ 123456wehi.edu.au

[b ] vaux@ 123456wehi.edu.au

Competing interests: DLV was on the scientific advisory board of TetraLogic, and he and NL have patent applications related to birinapant.

Author information

Najoua Lalaoui https://orcid.org/0000-0002-0165-3324

Article

DOI: 10.12688/f1000research.16439.1

PMC ID: 6281012

SO-VID: c50dcc09-a3b1-4897-80be-a67c04ec7688

License:

This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date accepted : 23 November 2018

Funding

Funded by: Cancer Australia and Cure Cancer Australia Foundation

Award ID: Projectgrant#1145588toNL

Funded by: National Health and Medical Research Council

Award ID: ProgramGrant#1113133toDLV

Funded by: Victorian Cancer Agency

Award ID: Fellowship#17030toNL

Funded by: National Health and Medical Research Council

Award ID: Fellowship#1020136toDLV

Funded by: Australian Government Independent Medical Research Institutes Infrastructure Support Scheme (IRIISS)

Funded by: Leukemia and Lymphoma Society SCOR

Award ID: Projectgrant#7001-13toDLV

Funded by: Victorian State Government Operational Infrastructure Support (OIS).

This work was supported by project grant #1145588 from the Cancer Australia and Cure Cancer Australia Foundation (to NL), Victorian Cancer Agency Mid-career Fellowship #17030 (to NL), Australian National Health and Medical Research Council (NHMRC) Program Grant #1113133 (to DLV), NHMRC Fellowship #1020136 (to DLV), and Leukemia and Lymphoma Society SCOR grant #7001-13 (to DLV). This work was made possible by operational infrastructure grants through the Australian government’s Independent Research Institute Infrastructure Support Scheme and the Victorian state government’s Operational Infrastructure Support.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Recent advances in understanding inhibitor of apoptosis proteins

Read this article at

Abstract

Related collections

Biomarkers for Inflammatory Lung Disease

Most cited references 138

Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL

Author and article information

Contributors

Journal

Affiliations

Author notes

Author information

Article

History

Funding

Categories

Comments

Comment on this article

Similar content 298

Cited by 35

Most referenced authors 3,822