Inhibitor of Apoptosis Protein cIAP2 Is Essential for Lipopolysaccharide-Induced Macrophage Survival

Conte, Damiano; Holčı́k, Martin; Lefebvre, Charles; LaCasse, Eric C.; Picketts, David J.; Wright, Kathryn; Korneluk, Robert G.

doi:10.1128/mcb.26.2.699-708.2006

Cited by 182 publications

(183 citation statements)

References 28 publications

Supporting

Mentioning

161

Contrasting

Unclassified

Order By: Relevance

“…Another study has shown that cIAP2-deficient mice are highly resistant to LPS-induced shock due to elevated macrophage cell death. 40 We reveal that the underlying mechanism of the findings in these studies may be increased macrophage necroptosis. It has also recently been shown that a mutation in the caspase-11 gene is present cIAP1 À / À mice.…”

Section: Discussionmentioning

confidence: 69%

See 1 more Smart Citation

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

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 69%

“…C57BL/6J mice and TNFR1/2 À / À (Jax #003243) were obtained at 4-8 weeks of age from Jackson Labs (Bar Harbor, ME, USA). Ageand sex-matched cIAP1 À / À , 44 cIAP2 À / À , 40 and WT C57BL/6J were used for in vivo infection and bone marrow macrophage experiments. xIAP mice were also utilized with age-matched control (C57BL/6J) mice.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

show abstract

“…20 Likewise, targeted gene disruption of cIAP1 and cIAP2 has not revealed any significant apoptotic phenotypes. 21,22 Although these results could be interpreted to indicate that IAPs do not play a major role for caspase regulation in mammals, a more likely alternative is that their physiological role is masked by functional redundancy. If relatively short-lived organisms such as fruit flies protect themselves against unwanted death using multiple caspase inhibitors (see below; Figure 1), 6,[8][9][10][11][12][13][14][15][23][24][25][26][27][28][29][30][31][32][33][34][35] it would come as a great surprise if mammals would employ fewer safeguards to control caspase activity.…”

Section: Brakes On Death: Caspase Inhibition By Inhibitor Of Apoptosimentioning

confidence: 90%

Regulation of apoptosis in Drosophila

2008

View full text Add to dashboard Cite

Insects have made major contributions to understanding the regulation of cell death, dating back to the pioneering work of Lockshin and Williams on death of muscle cells during postembryonic development of Manduca. A physically smaller cousin of moths, the fruit fly Drosophila melanogaster, offers unique advantages for studying the regulation of cell death in response to different apoptotic stimuli in situ. Different signaling pathways converge in Drosophila to activate a common death program through transcriptional activation of reaper, hid and grim. Reaper-family proteins induce apoptosis by binding to and antagonizing inhibitor of apoptosis proteins (IAPs), which in turn inhibit caspases. This switch from life to death relies extensively on targeted degradation of cell death proteins by the ubiquitin-proteasome pathway. Drosophila IAP-1 (Diap1) functions as an E3-ubiquitin ligase to protect cells from unwanted death by promoting the degradation of the initiator caspase Dronc. However, in response to apoptotic signals, Reaper-family proteins are produced, which promote the auto-ubiquitination and degradation of Diap1, thereby removing the 'brakes on death' in cells that are doomed to die. More recently, several other ubiquitin pathway proteins were found to play important roles for caspase regulation, indicating that the control of cell survival and death relies extensively on targeted degradation by the ubiquitin-proteasome pathway.

show abstract

“…Subsequent overexpression studies showed that cIAP2 has the capacity to activate NF-B (6) and that a RING-deficient version of cIAP1 can cooperate in the activation of NF-B by TRAF2 (3). More recently, however, their involvement in NF-B signaling has been called into question, because studies in cIAP1 and 2 null mice have not supported such a role (20,21). Mice with whole-body deletion of cIAP1 are asymptomatic, and the primary cells tested from these animals display normal TNF␣-induced NF-B activation and are not sensitized to TNF␣-mediated cell death (21).…”

Section: Apoptosis ͉ Receptor Interacting Protein (Rip1)mentioning

confidence: 99%

Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation

Mahoney

Cheung

Mrad

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

480

410

View full text Add to dashboard Cite

The cellular inhibitor of apoptosis 1 and 2 (cIAP1 and cIAP2) proteins have been implicated in the activation of NF-B by TNF␣; however, genetic deletion of either cIAP1 or 2 did not support a physiologically relevant role, perhaps because of functional redundancy. To address this, we used combined genetic and siRNA knockdown approaches and report that cIAP1 and 2 are indeed critical, yet redundant, regulators of NF-B activation upon TNF␣ treatment. Whereas NF-B was properly activated by TNF␣ in cultured and primary cells deficient in either cIAP1 or 2, removal of both cIAPs severely blunted its activation. After treatment with TNF␣, cIAP1 and 2 were rapidly recruited to the TNF receptor 1, along with the adapter protein TNF receptor associated factor 2. Importantly, either cIAP1 or 2 was required for proper TNF receptor 1 signalosome function. In their combined absence, polyubiquitination of receptor interacting protein 1, an upstream event necessary for NF-B signaling, was attenuated. As a result, phosphorylation of the inhibitor of B kinase ␤ was diminished, and signal transduction was severely blunted. Consequently, cells missing both cIAP1 and 2 were sensitized to TNF␣-mediated apoptosis.Collectively, these data demonstrate that either cIAP1 or 2 is required for proper Rip1 polyubiquitination and NF-B activation upon TNF␣ treatment.apoptosis ͉ Receptor Interacting Protein (RIP1)

show abstract

Inhibitor of Apoptosis Protein cIAP2 Is Essential for Lipopolysaccharide-Induced Macrophage Survival

Cited by 182 publications

References 28 publications

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

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

Regulation of apoptosis in Drosophila

Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation

Contact Info

Product

Resources

About