Apoptosis and Autoimmune Disorders

Halaby, Reginald

doi:10.5772/48164

Cited by 4 publications

(2 citation statements)

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“…Additionally, the mechanisms have been uncovered in recent years by which inflammatory caspases promote pyroptosis, another major lytic cell death mode that is associated with the secretion of the inflammatory cytokines interleukin (IL)-1b and IL-18 (Vande Walle and Lamkanfi, 2016). An extensive body of evidence from the past three decades has implicated dysregulated caspase activation as a causal disease mechanism in tumorigenesis, autoimmunity, autoinflammation and infectious pathologies (Halaby, 2012;Van Gorp et al, 2019). Here, we will succinctly review the roles and signaling mechanisms of apoptotic caspases to then focus the discussion on recent insights on activation mechanisms of inflammatory caspases and the diverse roles of caspases in cell death and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Caspases in Cell Death, Inflammation, and Disease

2019

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Caspases are an evolutionary conserved family of cysteine proteases that are centrally involved in cell death and inflammation responses. A wealth of foundational insight into the molecular mechanisms that control caspase activation has emerged in recent years. Important advancements include the identification of additional inflammasome platforms and pathways that regulate activation of inflammatory caspases; the discovery of gasdermin D as the effector of pyroptosis and interleukin (IL)-1 and IL-18 secretion; and the existence of substantial crosstalk between inflammatory and apoptotic initiator caspases. A better understanding of the mechanisms regulating caspase activation has supported initial efforts to modulate dysfunctional cell death and inflammation pathways in a suite of communicable, inflammatory, malignant, metabolic, and neurodegenerative diseases. Here, we review current understanding of caspase biology with a prime focus on the inflammatory caspases and outline important topics for future experimentation.

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Section: Introductionmentioning

confidence: 99%

Caspases in Cell Death, Inflammation, and Disease

2019

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“…Caspases were first identified as regulators of apoptosis, but are now known to regulate other cellular processes such as immune signalling and development. Dysregulation of caspases has been implied in tumorigenesis, autoimmunity, autoinflammation and infectious pathologies , Halaby, 2012, Van Gorp et al, 2019. Caspases are known to be regulated by IAP proteins, however, regulation of the activity of IAP proteins by caspases has not been established before.…”

Section: Discussionmentioning

confidence: 99%

drICE restrains DIAP2-mediated inflammatory signalling and intestinal inflammation

Kietz

Pollari

Tuominen

et al. 2020

Preprint

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AbstractThe Drosophila IAP protein, DIAP2, is a key mediator of NF-κB signalling and is required for immune activation, both locally in the intestinal epithelia and during systemic, fat body-induced responses. We have found that transgenic expression of DIAP2 induces inflammation in the intestine, but not in the fat body, indicating a need for regulating DIAP2 in microbiotic environments. We describe the Drosophila caspase drICE, a known interaction partner of DIAP2, as a regulator of DIAP2 and NF-κB signalling in the intestinal epithelium. drICE acts by cleaving, and interfering with DIAP2’s ability to ubiquitinate and, thereby, activate mediators of the NF-κB pathway. The drICE-cleaved form of DIAP2 is, moreover, unable to induce inflammation during basal conditions in the intestine. Interestingly, cleavage of DIAP2 does not interfere with pathogen-induced signalling, suggesting that drICE protects from immune responses induced by resident microbes. Accordingly, the negative regulatory effect of drICE is lost when rearing flies axenic. Hence, we show that drICE halts unwanted inflammatory signalling in the intestine by forming an inhibitory complex with DIAP2, interfering with the ability of DIAP2 to induce downstream signalling and NF-κB target gene activation.

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