title: cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation.
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.
authors.affiliation: NRC-Institute for Biological Sciences, Ottawa, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: McComb
authors.forename: H H
authors.initials: HH
authors.lastname: Cheung
authors.forename: R G
authors.initials: RG
authors.lastname: Korneluk
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Krishnan
authors.forename: S
authors.initials: S
authors.lastname: Sad
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D040761:Biomimetic Materials / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D020690:GTPase-Activating Proteins; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; C490620:Ralbp1 protein, mouse; D018124:Receptors, Tumor Necrosis Factor; C533467:SM 164; D014230:Triazoles; D051636:X-Linked Inhibitor of Apoptosis Protein; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse