Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation

Zhang, Jieqiong; Webster, Joshua D.; Dugger, Debra L.; Goncharov, Tatiana; Roose‐Girma, Merone; Hung, J. H.; Kwon, Youngsu; Vucic, Domagoj; Newton, Kim; Dixit, Vishva M.

doi:10.1016/j.celrep.2019.04.111

Cited by 52 publications

(49 citation statements)

References 77 publications

(100 reference statements)

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“…The specific polyubiquitination pattern on RIP1 that keeps it in complex I for proper downstream activation of NF-κB and MAPKs is fine-tuned by the activation of E3 ligases, such as c-IAP1/2 ( Bertrand et al, 2008 ; Mahoney et al, 2008 ; Varfolomeev et al, 2008 ; Silke and Vucic, 2014 ). The combined deletion of c-IAP1 and c-IAP2 in mice results in embryonic lethality and severe liver and intestinal damage in the adulthood, which can be rescued by TNFR1 knock-out or by TNF blockade, further emphasizing the functional and genetic relationship between these E3 ligases and TNF signaling ( Moulin et al, 2012 ; Zhang J. et al, 2019 ). However, these complexes are also governed through negative regulation by deubiquitinases (DUBs).…”

Section: Activation Of Nf-κb and Mapk Signaling By Tnfmentioning

confidence: 99%

“…Inducible inactivation of OTULIN’s DUB function in adult mice results in extensive hepatocyte and intestinal crypt cell death, and inflammation, primarily driven by myeloid cells, in the heart and liver ( Heger et al, 2018 ). Similarly, co-deletion of Birc2 and Birc3 , which encode c-IAP1 and c-IAP2, respectively, in adult mice results in extensive hepatocyte death and crypt degeneration with intestinal villous atrophy and secondary inflammation ( Zhang J. et al, 2019 ). In both OTULIN and c-IAP1/2 deficient mice, cell death in the liver and intestines was associated with extensive cleaved caspase-3 immunolabeling, suggesting a predominance of apoptosis ( Heger et al, 2018 ; Zhang J. et al, 2019 ).…”

Section: Deciphering Tnf Signaling Regulation Through Genetic Mouse Mmentioning

confidence: 99%

“…Similarly, co-deletion of Birc2 and Birc3 , which encode c-IAP1 and c-IAP2, respectively, in adult mice results in extensive hepatocyte death and crypt degeneration with intestinal villous atrophy and secondary inflammation ( Zhang J. et al, 2019 ). In both OTULIN and c-IAP1/2 deficient mice, cell death in the liver and intestines was associated with extensive cleaved caspase-3 immunolabeling, suggesting a predominance of apoptosis ( Heger et al, 2018 ; Zhang J. et al, 2019 ). While loss of RIP3 alone does not prevent lesions in either mouse, loss of caspase-8 and RIP3 rescued both the cell death and, to a significant degree, the associated inflammation.…”

Section: Deciphering Tnf Signaling Regulation Through Genetic Mouse Mmentioning

confidence: 99%

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The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues

Webster¹,

Vucic²

2020

Front. Cell Dev. Biol.

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204

125

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Tumor necrosis factor alpha (TNF; TNFα) is a critical regulator of immune responses in healthy organisms and in disease. TNF is involved in the development and proper functioning of the immune system by mediating cell survival and cell death inducing signaling. TNF stimulated signaling pathways are tightly regulated by a series of phosphorylation and ubiquitination events, which enable timely association of TNF receptors-associated intracellular signaling complexes. Disruption of these signaling events can disturb the balance and the composition of signaling complexes, potentially resulting in severe inflammatory diseases.

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Section: Activation Of Nf-κb and Mapk Signaling By Tnfmentioning

confidence: 99%

Section: Deciphering Tnf Signaling Regulation Through Genetic Mouse Mmentioning

confidence: 99%

Section: Deciphering Tnf Signaling Regulation Through Genetic Mouse Mmentioning

confidence: 99%

See 1 more Smart Citation

The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues

Webster¹,

Vucic²

2020

Front. Cell Dev. Biol.

Self Cite

204

125

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“…Aberrant caspase‐8 activity has been implicated in a variety of inflammatory diseases and, in some cases, can even drive lethality. For example, caspase‐8 drives lethal dermatitis in the absence of linear ubiquitin chain assembly complex (LUBAC; Taraborrelli et al , ), and caspase‐8 activity triggers embryonic lethality observed in Birc2 −/− Birc3 −/− mice (Zhang et al , ). Furthermore, caspase‐8‐dependent intestinal damage is a key driver for septic shock in mice (Mandal et al , ).…”

Section: Introductionmentioning

confidence: 99%

Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis

2019

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Programmed cell death is a key mechanism involved in several biological processes ranging from development and homeostasis to immunity, where it promotes the removal of stressed, damaged, malignant or infected cells. Abnormalities in the pathways leading to initiation of cell death or removal of dead cells are consequently associated with a range of human diseases including infections, autoinflammatory disease, neurodegenerative disease and cancer. Apoptosis, pyroptosis and NETosis are three well-studied modes of cell death that were traditionally believed to be independent of one another, but emerging evidence indicates that there is extensive cross-talk between them, and that all three pathways can converge onto the activation of the same cell death effector-the pore-forming protein Gasdermin D (GSDMD). In this review, we highlight recent advances in gasdermin research, with a particular focus on the role of gasdermins in pyroptosis, NETosis and apoptosis, as well as cell type-specific consequences of gasdermin activation. In addition, we discuss controversies surrounding a related gasdermin family protein, Gasdermin E (GSDME), in mediating pyroptosis and secondary necrosis following apoptosis, chemotherapy and inflammasome activation.Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535: 111 -116

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“…The observed downregulation of the IAP family and RIP1 in the Pd(T4) model exhibits the temporal nature of PDT-elicited activity. CIAP 1/2 is known to act as a ubiquitin ligase inhibiting RIP1 through proteosomal degradation [66]. This activity seems to happen before the IAP family is complexed with Smac [67], following its release from the mitochondria via MOMP induced by PDI and Bax.…”

Section: Discussionmentioning

confidence: 99%

Metalloporphyrin Pd(T4) Exhibits Oncolytic Activity and Cumulative Effects with 5-ALA Photodynamic Treatment against C918 Cells

Leviskas

Vályi-Nagy

Munirathinam

et al. 2020

IJMS

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Photodynamic therapy is a non-invasive method where light activates a photosensitizer bound to cancer cells, generating reactive oxygen species and resulting in cell death. This study assessed the oncolytic potential of photodynamic therapy, comparing European Medicines Agency and United States Food and Drug Administration-approved 5-aminolevulinic acid (5-ALA) to a metalloporphyrin, Pd(T4), against a highly invasive uveal melanoma cell line (C918) in two- and three-dimensional models in vitro. Epithelial monolayer studies displayed strong oncolytic effects (>70%) when utilizing Pd(T4) at a fraction of the concentration, and reduced pre-illumination time compared to 5-ALA post-405 nm irradiance. When analyzed at sub-optimal concentrations, application of Pd(T4) and 5-ALA with 405 nm displayed cumulative effects. Lethality from Pd(T4)-photodynamic therapy was maintained within a three-dimensional model, including the more resilient vasculogenic mimicry-forming cells, though at lower rates. At high concentrations, modality of cell death exhibited necrosis partially dependent on reactive oxygen species. However, sub-optimal concentrations of photosensitizer exhibited an apoptotic protein expression profile characterized by increased Bax/Bcl-2 ratio and endoplasmic stress-related proteins, along with downregulation of apoptotic inhibitors CIAP-1 and -2. Together, our results indicate Pd(T4) as a strong photosensitizer alone and in combination with 5-ALA against C918 cells.

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Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation

Abstract: Highlights d Acute cIAP1/2 deficiency in adult mice unleashes apoptosis and inflammation d cIAP1/2 limit inflammation by suppressing the activation of caspase-8 d cIAP1/2 also prevent embryonic lethality by limiting caspase-8-dependent cell death

Cited by 52 publications

References 77 publications

The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues

The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues

Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis

Metalloporphyrin Pd(T4) Exhibits Oncolytic Activity and Cumulative Effects with 5-ALA Photodynamic Treatment against C918 Cells

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