Caspase 1 Activation Is Protective against Hepatocyte Cell Death by Up-regulating Beclin 1 Protein and Mitochondrial Autophagy in the Setting of Redox Stress

Sun, Qian; Gao, Wentao; Loughran, Patricia; Shapiro, Rick; Fan, Jie; Billiar, Timothy R.; Scott, Melanie J.

doi:10.1074/jbc.m112.426791

Cited by 74 publications

(84 citation statements)

References 43 publications

(47 reference statements)

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“…In the first model, AIM2 activation by host-derived dsDNA led to increased autophagic flux in hepatocytes after redox stress induced by hypoxia with reoxygenation (13). Moreover, in vivo induction of autophagy by AIM2 inflammasome was protective by inducing removal of ROS-generating mitochondria in the liver (13,53). Similar to the previous study with RalB, beclin1 was an important mediator in autophagy activation mediated by AIM2 (13,53).…”

Section: Selective Autophagy In Inflammasome Activationsupporting

confidence: 69%

Inflammasome and Autophagy Regulation: A Two-way Street

Sun

Fan

Billiar

et al. 2017

Mol Med

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168

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Inflammation plays a significant role in protecting hosts against pathogens. Inflammation induced by noninfectious endogenous agents can be detrimental and, if excessive, can result in organ and tissue damage. The inflammasome is a major innate immune pathway that can be activated via both exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). Inflammasome activation involves formation and oligomerization of a protein complex including a nucleotide oligomerization domain (NOD)-like receptor (NLR), an adaptor protein and pro-caspase-1. This then allows cleavage and activation of caspase-1, followed by downstream cleavage and release of proinflammatory cytokines interleukin (IL)-1β and IL-18 from innate immune cells. Hyperinflammation caused by unrestrained inflammasome activation is linked with multiple inflammatory diseases, including inflammatory bowel disease, Alzheimer's disease and multiple sclerosis. So there is an understandable rush to understand mechanisms that regulate such potent inflammatory pathways. Autophagy has now been identified as a main regulator of inflammasomes. Autophagy is a vital intracellular process involved in cellular homeostasis, recycling and removal of damaged organelles (eg, mitochondria) and intracellular pathogens. Autophagy is regulated by proteins that are important in endosomal/phagosomal pathways, as well as by specific autophagy proteins coded for by autophagy-related genes. Cytosolic components are surrounded and contained by a double-membraned vesicle, which then fuses with lysosomes to enable degradation of the contents. Autophagic removal of intracellular DAMPs, inflammasome components or cytokines can reduce inflammasome activation. Similarly, inflammasomes can regulate the autophagic process, allowing for a two-way mutual regulation of inflammation that may hold the key for treatment of multiple diseases.

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Section: Selective Autophagy In Inflammasome Activationsupporting

confidence: 69%

Inflammasome and Autophagy Regulation: A Two-way Street

Sun

Fan

Billiar

et al. 2017

Mol Med

Self Cite

168

133

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“…Additionally, a role of caspase-1 in facilitation of cytoprotective autophagy has been suggested during hypoxia-induced mitochondrial stress [67]. In hepatocytes of casp-1 -/ -mice levels of the common autophagy markers LC3 and Beclin-1 were found to be decreased compared to wild-type (WT) [67]. When Beclin-1 was overexpressed in these cells the group reported that impaired autophagic clearance of damaged mitochondria was restored to WT rates [67].…”

Section: Initiator Caspasesmentioning

confidence: 95%

Section: Initiator Caspasesmentioning

confidence: 99%

“…In hepatocytes of casp-1 -/ -mice levels of the common autophagy markers LC3 and Beclin-1 were found to be decreased compared to wild-type (WT) [67]. When Beclin-1 was overexpressed in these cells the group reported that impaired autophagic clearance of damaged mitochondria was restored to WT rates [67]. It was therefore suggested that aside from its role in immune cells, caspase-1 in murine hepatocytes appears to favor autophagy and clearance of damaged mitochondria after redox stress by activating LC3 and Beclin-1 through an as-of-yet undefined mechanism [67].…”

Section: Initiator Caspasesmentioning

confidence: 99%

“…Caspase-1 is primarily involved in the maturation of the pro-inflammatory cytokines interleukin-1B/interleukin-18 during oxidative stress in immune cells and endothelial cells [67], [69]. Additionally, a role of caspase-1 in facilitation of cytoprotective autophagy has been suggested during hypoxia-induced mitochondrial stress [67].…”

Section: Initiator Caspasesmentioning

confidence: 99%

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Caspase involvement in autophagy

2017

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Caspases are a family of cysteine proteases widely known as the principal mediators of the apoptotic cell death response, but considerably less so as the contributors to the regulation of pathways outside cellular demise. In regards to autophagy, the modulatory roles of caspases have only recently begun to be adequately described. In contrast to apoptosis, autophagy promotes cell survival by providing energy and nutrients through the lysosomal degradation of cytoplasmic constituents. Under basal conditions autophagy and apoptosis cross-regulate each other through an elaborate network of interconnections which also includes the interplay between autophagyrelated proteins (ATGs) and caspases. In this review we focus on the effects of this crosstalk at the cellular level, as we aim to concentrate the main observations from research conducted so far on the fine-tuning of autophagy by caspases. Several members of this protease-family have been found to directly interact with key ATGs involved in different tiers across the autophagic cascade. Therefore, we firstly outline the core mechanism of macroautophagy in brief. In an effort to emphasize the importance of the intricate cross-regulation of ATGs and caspases, we also present examples drawn from Drosophila and plant models regarding the contribution of autophagy to apoptotic cell death during normal development. Keywords and abbreviationsautophagy; macroautophagy; mammals; caspases; apoptosis; crosstalk; regulation AMBRA-1Activating-molecule-in-Beclin1-regulated-autophagy-1 AMPK AMP-activated-protein-kinase ATG Autophagy-related gene ATG14L ATG14-likeBcl-2 B-cell lymphoma 2 • Autophagy is implicated in many physiological and pathological processes, where apoptosis is also involved DISC Death-inducing signalling complex FADD Fas-associated protein with death domain Open Questions• Does control of autophagy by caspases represent a central or a supplementary mode of regulation of this pathway?• Is caspase activation required to control autophagy?• To what extent do caspases affect autophagy and how exactly their effects on the pathway vary across different contexts?4

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Hepatocyte-specific high-mobility group box 1 deletion worsens the injury in liver ischemia/reperfusion: A role for intracellular high-mobility group box 1 in cellular protection

et al. 2014

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High-mobility group box 1 (HMGB1) is an abundant chromatin-associated nuclear protein and released into the extracellular milieu during liver ischemia-reperfusion (I/R), signaling activation of proinflammatory cascades. Because the intracellular function of HMGB1 during sterile inflammation of I/R is currently unknown, we sought to determine the role of intracellular HMGB1 in hepatocytes after liver I/R. When hepatocytespecific HMGB1 knockout (HMGB1-HC-KO) and control mice were subjected to a nonlethal warm liver I/R, it was found that HMGB1-HC-KO mice had significantly greater hepatocellular injury after I/R, compared to control mice. Additionally, there was significantly greater DNA damage and decreased chromatin accessibility to repair with lack of HMGB1. Furthermore, lack of hepatocyte HMGB1 led to excessive poly(ADP-ribose)polymerase 1 activation, exhausting nicotinamide adenine dinucleotide and adenosine triphosphate stores, exacerbating mitochondrial instability and damage, and, consequently, leading to increased cell death. We found that this was also associated with significantly more oxidative stress (OS) in HMGB1-HC-KO mice, compared to control. Increased nuclear instability led to a resultant increase in the release of histones with subsequently more inflammatory cytokine production and organ damage through activation of Toll-like receptor 9. Conclusion: The lack of HMGB1 within hepatocytes leads to increased susceptibility to cellular death after OS conditions.

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Caspase 1 Activation Is Protective against Hepatocyte Cell Death by Up-regulating Beclin 1 Protein and Mitochondrial Autophagy in the Setting of Redox Stress

Cited by 74 publications

References 43 publications

Inflammasome and Autophagy Regulation: A Two-way Street

Inflammasome and Autophagy Regulation: A Two-way Street

Caspase involvement in autophagy

Hepatocyte-specific high-mobility group box 1 deletion worsens the injury in liver ischemia/reperfusion: A role for intracellular high-mobility group box 1 in cellular protection

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