Abstract
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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Abbreviations
- cIAP:
-
cellular inhibitors of apoptotic proteins
- xIAP:
-
x-linked inhibitor of apoptosis protein
- FLIP:
-
FLICE-like inhibitory protein
- SMAC:
-
second mitochondria-derived activator of caspases
- RIP:
-
receptor interacting protein
- TNF:
-
tumor necrosis factor
- Nec-1:
-
necrostatin-1
- ROS:
-
reactive oxygen species
- FADD:
-
Fas-associated death domain
- LM:
-
Listeria monocytogenes
- BMDMs:
-
bone-marrow-derived macrophages
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Acknowledgements
This work was supported by grants from the Canadian Institutes of Health Research (SS) and the Ontario Institute for Cancer Research (LK).
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McComb, S., Cheung, H., Korneluk, R. et al. cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation. Cell Death Differ 19, 1791–1801 (2012). https://doi.org/10.1038/cdd.2012.59
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DOI: https://doi.org/10.1038/cdd.2012.59
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