Cleaving Beclin 1 to suppress autophagy in chemotherapy-induced apoptosis

Li, Hua; Wang, Peng; Yu, Jian; Zhang, Lin

doi:10.4161/auto.7.10.16490

Cited by 30 publications

(27 citation statements)

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“…Studies have indicated that cleaved beclin-1 fails to induce autophagy but can associate with mitochondria to induce apoptosis. 68,69 In conclusion, the correlation between ineffective bacterial Figure 7 IFNAR1 signaling increased the numbers of IL-10eproducing-CD3 þ CD4 þ CD25 þ T cells and the number of FOXP3-expressing Tregs in liver during fatal ehrlichial infection. A: Flow cytometry analysis of the percentage of CD3 þ CD4 þ CD25 þ and IL-10 þ CD3 þ CD4 þ CD25 þ T cells in spleen at day 7 p.i.…”

Section: Ehrlichiae Block Autophagy Processing That Is Dependent On Imentioning

confidence: 96%

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Type I Interferon Contributes to Noncanonical Inflammasome Activation, Mediates Immunopathology, and Impairs Protective Immunity during Fatal Infection with Lipopolysaccharide-Negative Ehrlichiae

Yang

Stevenson

Scott

et al. 2015

The American Journal of Pathology

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Ehrlichia species are intracellular bacteria that cause fatal ehrlichiosis, mimicking toxic shock syndrome in humans and mice. Virulent ehrlichiae induce inflammasome activation leading to caspase-1 cleavage and IL-18 secretion, which contribute to development of fatal ehrlichiosis. We show that fatal infection triggers expression of inflammasome components, activates caspase-1 and caspase-11, and induces host-cell death and secretion of IL-1b, IL-1a, and type I interferon (IFN-I). Wild-type and Casp1 À/À mice were highly susceptible to fatal ehrlichiosis, had overwhelming infection, and developed extensive tissue injury. Nlrp3 À/À mice effectively cleared ehrlichiae, but displayed acute mortality and developed liver injury similar to wild-type mice. By contrast, Ifnar1 À/À mice were highly resistant to fatal disease and had lower bacterial burden, attenuated pathology, and prolonged survival. Ifnar1 À/À mice also had improved protective immune responses mediated by IFN-g and CD4 þ Th1 and natural killer T cells, with lower IL-10 secretion by T cells. Importantly, heightened resistance of Ifnar1 À/À mice correlated with improved autophagosome processing, and attenuated noncanonical inflammasome activation indicated by decreased activation of caspase-11 and decreased IL-1b, compared with other groups. Our findings demonstrate that IFN-I signaling promotes host susceptibility to fatal ehrlichiosis, because it mediates ehrlichia-induced immunopathology and supports bacterial replication, perhaps via activation of noncanonical inflammasomes, reduced autophagy, and suppression of protective CD4 þ T cells and natural killer T-cell responses against ehrlichiae. (Am J Pathol 2015, 185: 446e461; http://dx.

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Section: Ehrlichiae Block Autophagy Processing That Is Dependent On Imentioning

confidence: 96%

“…Beclin-1 is an important protein that mediates autophagy initiation and nucleation, and its function is thought to be controlled by cleavage. 58,68 The WT mice and all knockout mice expressed similar levels of fulllength beclin-1 in the liver tissues on day 7 p.i. (Figure 11, A and C).…”

Section: Ehrlichiae Block Autophagy Processing That Is Dependent On Imentioning

confidence: 99%

Type I Interferon Contributes to Noncanonical Inflammasome Activation, Mediates Immunopathology, and Impairs Protective Immunity during Fatal Infection with Lipopolysaccharide-Negative Ehrlichiae

Yang

Stevenson

Scott

et al. 2015

The American Journal of Pathology

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“…A number of groups have observed caspase induced site specific cleavage of Beclin 1 following induction of apoptosis [27,28]. These results led to a hypothesis that Beclin 1cleavage may inhibit protective autophagy in cells committed to cell death.…”

Section: Regulation Of Apoptosis By Autophagy Proteinsmentioning

confidence: 99%

The role of cell signalling in the crosstalk between autophagy and apoptosis

Booth

Tavallai

Hamed

et al. 2014

Cellular Signalling

306

207

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Not surprisingly, the death of a cell is a complex and well controlled process. For several decades, apoptosis, the first genetically programmed death process to be identified has taken centre stage as the principal mechanism of programmed cell death (type I cell death) in mammalian tissues. Apoptosis has been extensively studied and its contribution to the pathogenesis of disease well documented. However, apoptosis does not function alone in determining the fate of a cell. More recently, autophagy, a process in which de novo formed membrane enclosed vesicles engulf and consume cellular components, has been shown to engage in complex interplay with apoptosis. As a result, cell death has been subdivided into the categories apoptosis (Type I), autophagic cell death (Type II), and necrosis (Type III). The boundary between Type I and II cell death is not completely clear and as we will discuss in this review and perhaps a discrete difference does not exist, due to intrinsic factors among different cell types and crosstalk among organelles within each cell type. Apoptosis may begin with autophagy and autophagy can often end with apoptosis, inhibition or a blockade of caspase activity may lead a cell to default into Type II cell death from Type I.

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“…Validation of the involvement of casp8 in autophagy came from studies showing that casp8 mediated the cleavage and subsequent inactivation of ATG3 and beclin 1 [43,44]. During TNF-related apoptosis-inducing ligand (TRAIL)-induced autophagy, the large catalytic subunit of casp8 was found to be degraded by the autophagosome [44,45]. These results suggest crosstalk between apoptosis and autophagy (Figure 1-2).…”

Section: Caspase-8mentioning

confidence: 97%

“…Yu et al further showed that the inhibition of casp8 was critical in order to induce autophagy mediated by ATG3 (autophagy-related gene 7) and beclin-1 [42]. Validation of the involvement of casp8 in autophagy came from studies showing that casp8 mediated the cleavage and subsequent inactivation of ATG3 and beclin 1 [43,44]. During TNF-related apoptosis-inducing ligand (TRAIL)-induced autophagy, the large catalytic subunit of casp8 was found to be degraded by the autophagosome [44,45].…”

Section: Caspase-8mentioning

confidence: 99%

The Protumorigenic Role of Caspase-8 in Neuroblastoma

Twitchell¹

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DEDICATIONThis dissertation is dedicated to my wonderful parents who have given immeasurable love, devotion, guidance, and sacrifice throughout the years on my behalf and have helped to make this achievement possible.A special dedication is extended to my lovely wife, who without her, none of this would have been possible. Through her unselfish love, devotion, and personal sacrifice for me and our family, she has been my strength, my support, and my motivation to endure when times got hard. To my wonderful children (Camryn, Leigha, Ethan, McKenna, and Hayden) who have kept me focused on what matters most in life.iv ACKNOWLEDGEMENTS This work would not have been possible without the mentorship of Dr. Jill Lahti, who lost her battle to breast cancer. Dr. Jill Lahti was a great mentor who allowed a young scientist, such as me, to explore and develop my technique, logic, and scientific reasoning. I regret that she could not be here to see this work completed. I appreciate her willingness to accept me into her lab and work on her project as my own. She was always willing to listen to my ideas and theories, no matter how extravagant, and always encouraged me to explore many of those ideas.Special thanks are extended to my current mentor Dr. Gerard Zambetti who was gracious enough to adopt me into his lab. I appreciate all the work he did behind the scenes to keep me at St. Jude long enough to complete my dissertation. Dr. Zambetti is an incredible mentor who is constantly urging me to challenge my hypothesis and myself as a researcher. He has given me great insight and understanding as to how be a good scientist, constantly questioning and challenging the hypothesis. Dr. Zambetti instilled in me a stronger desire to improve as a scientist each time we met. I am also very

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Cleaving Beclin 1 to suppress autophagy in chemotherapy-induced apoptosis

Abstract: RW, et al. Following cytochrome c release, autophagy is inhibited during chemotherapy-induced apoptosis by caspase 8-mediated cleavage of Beclin 1.

Cited by 30 publications

References 1 publication

Type I Interferon Contributes to Noncanonical Inflammasome Activation, Mediates Immunopathology, and Impairs Protective Immunity during Fatal Infection with Lipopolysaccharide-Negative Ehrlichiae

Type I Interferon Contributes to Noncanonical Inflammasome Activation, Mediates Immunopathology, and Impairs Protective Immunity during Fatal Infection with Lipopolysaccharide-Negative Ehrlichiae

The role of cell signalling in the crosstalk between autophagy and apoptosis

The Protumorigenic Role of Caspase-8 in Neuroblastoma

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