cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation
Open accessAbstract
Cellular inhibitor of apoptosis proteins (cIAPs) have emerged as important anti-cell death mediators, particularly in cancer. Although they are known to be expressed in immune tissue, their specific immune function remains unclear. We observed that degradation of cIAPs with SMAC mimetic (SM) results in death of primary bone-marrow-derived macrophages. SM-induced death of macrophages occurred by programmed necrosis (necroptosis), which was dependent on TNF receptor expression. Consistent with necroptosis, SM-induced death of macrophages was abrogated by inhibition of receptor interacting protein 1 (Rip1) kinase signaling or by receptor interacting protein 3 (Rip3) knockdown. SM-induced necroptosis was also dependent on inhibition of SM-induced apoptosis due to the expression of the endogenous caspase inhibitor, xIAP. We found that cIAPs limit Rip3, and to a lesser extent Rip1, expression via post-transcriptional mechanisms, leading to inhibition of the Rip1-Rip3 death complex (necrosome). Reduced cIAP activity in vivo, via SM treatment or specific knockout of either cIAP, resulted in elevated macrophage cell death and compromised control of an intracellular bacterium, Listeria monocytogenes. These results show that cIAPs have an important role in limiting programmed necrosis of macrophages, which facilitates effective control of a pathogen.
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Necroptosis is tonically inhibited by c-IAPs, owing to their ability to ubiquitinate RIPK1.
“Necroptosis is also tonically inhibited by c-IAPs, owing to their ability to ubiquitinate RIPK1 [490–493].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [490]
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- Authors
- McComb, S., Cheung, H. H., Korneluk, R. G., Wang, S., Krishnan, L., & Sad, S.
- Affiliations
- Institute for Biological Sciences (CA)
- University of Ottawa (CA)
- University of Michigan (US)
- Corresponding author
- Sad, S
- Venue
- Cell Death & Differentiation
- Published
- 2012-05-11
- Volume
- 19
- Issue
- 11
- Pages
- 1791-1801
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3469059
- OpenAlex
- W2093852411
- Cited by
- 148
- References
- 45
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 4 · 2023: 9 · 2022: 12 · 2021: 5 · 2020: 12 · 2019: 8 · 2018: 9 · 2017: 14 · 2016: 8 · 2015: 15 · 2014: 16 · 2013: 13 · 2012: 9
- FWCI
- 6.81
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- NPARC (acceptedVersion)
- Funders
- Ontario Institute for Cancer Research
- Canadian Institutes of Health Research (79412, 87055)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- cIAP1, cIAP2, necroptosis, macrophages, RIPK1, RIPK3, necrosome, IAP antagonists, XIAP, TNF receptor signaling, Listeria monocytogenes, innate immunity, post-transcriptional regulation, bone marrow-derived macrophages
- MeSH terms
- Baculoviral IAP Repeat-Containing 3 Protein, Animals, Cells, Cultured, Macrophages, Mice, Inbred C57BL, Necrosis, Triazoles, Apoptosis, Receptors, Tumor Necrosis Factor, Mice, Knockout, Bridged Bicyclo Compounds, Heterocyclic, GTPase-Activating Proteins, RNA Interference, RNA, Small Interfering, Biomimetic Materials, Ubiquitin-Protein Ligases, Inhibitor of Apoptosis Proteins, Mice, X-Linked Inhibitor of Apoptosis Protein, Receptor-Interacting Protein Serine-Threonine Kinases
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