Intertwined pathways of programmed cell death in immunity

Hedrick, Stephen M.; Ch’en, Irene L.; Alves, Bryce N.

doi:10.1111/j.1600-065x.2010.00918.x

Cited by 36 publications

(45 citation statements)

References 195 publications

(224 reference statements)

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“…c-FLIP is a direct inhibitor of caspase-8, whereas caspase-8 is known to transmit activation signals (39,40). Additionally, TLR3, TLR4, and dectin-1 have been shown to trigger IL-1b production in the caspase-8-dependent pathway (41,42).…”

Section: The Suppressive Activity Of C-flip Is Caspase-8-independentmentioning

confidence: 99%

Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling

et al. 2015

The Journal of Immunology

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Cellular FLIP (c-FLIP) specifically inhibits caspase-8 and suppresses death receptor–induced apoptosis. c-FLIP has also been reported to transmit activation signals. In this study, we report a novel function of c-FLIP involving inhibition of myeloid cell activation through antagonizing the selective innate signaling pathway. We found that conditional knockout of c-FLIP in dendritic cells (DCs) led to neutrophilia and splenomegaly. Peripheral DC populations, including CD11b+ conventional DCs (cDCs), CD8+ cDCs, and plasmacytoid DCs, were not affected by c-FLIP deficiency. We also found that c-FLIP knockout cDCs, plasmacytoid DCs, and bone marrow–derived DCs (BMDCs) displayed enhanced production of TNF-α, IL-2, or G-CSF in response to stimulation of TLR4, TLR2, and dectin-1. Consistent with the ability of c-FLIP to inhibit the activation of p38 MAPK, the enhanced activation of c-FLIP–deficient BMDCs could be partly linked to an elevated activation of p38 MAPK after engagement of innate receptors. Increased activation was also found in c-FLIP+/− macrophages. Additionally, the increased activation in c-FLIP–deficient DCs was independent of caspase-8. Our results reveal a novel inhibitory role of c-FLIP in myeloid cell activation and demonstrate the unexpected anti-inflammatory activity of c-FLIP. Additionally, our observations suggest that cancer therapy targeting c-FLIP downregulation may facilitate DC activation and increase T cell immunity.

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Section: The Suppressive Activity Of C-flip Is Caspase-8-independentmentioning

confidence: 99%

Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling

et al. 2015

The Journal of Immunology

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“…19 Among the various roles of PCD in maintaining the homeostasis of living organisms is its involvement in the advancement of immune responses. [20][21][22] In fact, the development of adaptive and innate immune responses depends on strict regulation of PCD signaling pathways, which are crucial for shaping and maintaining the immune system and ensuring functional immune responses. [20][21][22] For example, PCD is involved in clonal deletion of lymphocytes during an infection, whereas the misregulation of PCD is known to lead to the defective clearance of autoreactive T cells and autoimmune disease.…”

mentioning

confidence: 99%

“…[20][21][22] In fact, the development of adaptive and innate immune responses depends on strict regulation of PCD signaling pathways, which are crucial for shaping and maintaining the immune system and ensuring functional immune responses. [20][21][22] For example, PCD is involved in clonal deletion of lymphocytes during an infection, whereas the misregulation of PCD is known to lead to the defective clearance of autoreactive T cells and autoimmune disease. 23 Figure 1 represents some major events taking place within a cell undergoing apoptosis, or autophagy, or necroptosis and clearly shows that these three types of PCD are heavily interlinked.…”

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confidence: 99%

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

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It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.

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“…The mechanisms of PCD in animals have been widely investigated and well documented (Hedrick, Ch'en, & Alves, 2010), whereas little is acquired about the control of plant PCD. Over the past decade, reports found that early calcium flux, mitochondrial release of apoptogenic proteins (such as cytochrome c), activation of caspase-like proteases or metacaspases, are key factors in the utmost destruction of the plant cell (Reape & McCabe, 2010).…”

Section: Introductionmentioning

confidence: 99%