cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation

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DOIResolve DOI: http://doi.org/10.1038/cdd.2012.59
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TypeArticle
Journal titleCell Death & Differentiation
ISSN1350-9047
1476-5403
Volume19
Issue11
Pages17911801; # of pages: 11
Subjectinnate immunity; macrophage; inflammation; host–pathogen interactions
AbstractCellular 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.
Publication date
LanguageEnglish
AffiliationHuman Health Therapeutics; National Research Council Canada
Peer reviewedYes
Identifiercdd201259
NPARC number21268912
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Record identifier0a43c3fc-109b-4cf4-9398-072c8b08570a
Record created2013-11-25
Record modified2016-05-09
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