Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis

Ebert, Gregor; Allison, Cody; Preston, Simon; Cooney, James P.; Toe, Jesse G.; Stutz, Michael D.; Ojaimi, Samar; Baschuk, Nikola; Nachbur, Ueli; Torresi, Joseph; Silke, John; Begley, C. Glenn; Pellegrini, Marc

doi:10.1073/pnas.1502400112

Cited by 108 publications

(117 citation statements)

References 25 publications

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“…Programmed cell death can also act to eliminate pathogen-infected cells, with recent studies highlighting how targeted apoptosis-inducing anticancer compounds can treat viral and intracellular bacterial infections (1,2). On the other hand, the recently characterized caspase-independent necroptotic cell death pathway is dispensable for organism development but, like apoptosis, can be triggered to kill cells harboring pathogenic microbes (3).…”

mentioning

confidence: 99%

Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner

Conos

Chen

Nardo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

351

298

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Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1β. Here, we provide evidence that MLKL-induced activation of NLRP3 requires (i) the death effector four-helical bundle of MLKL, (ii) oligomerization and association of MLKL with cellular membranes, and (iii) a reduction in intracellular potassium concentration. Although genetic or pharmacological targeting of NLRP3 or caspase-1 prevented MLKLinduced IL-1β secretion, they did not prevent necroptotic cell death. Gasdermin D (GSDMD), the pore-forming caspase-1 substrate required for efficient NLRP3-triggered pyroptosis and IL-1β release, was not essential for MLKL-dependent death or IL-1β secretion. Imaging of MLKL-dependent ASC speck formation demonstrated that necroptotic stimuli activate NLRP3 cell-intrinsically, indicating that MLKL-induced NLRP3 inflammasome formation and IL-1β cleavage occur before cell lysis. Furthermore, we show that necroptotic activation of NLRP3, but not necroptotic cell death alone, is necessary for the activation of NF-κB in healthy bystander cells. Collectively, these results demonstrate the potential importance of NLRP3 inflammasome activity as a driving force for inflammation in MLKLdependent diseases.aspase-dependent apoptotic cell death is required for mammalian development and the prevention of autoimmune and neoplastic diseases. Programmed cell death can also act to eliminate pathogen-infected cells, with recent studies highlighting how targeted apoptosis-inducing anticancer compounds can treat viral and intracellular bacterial infections (1, 2). On the other hand, the recently characterized caspase-independent necroptotic cell death pathway is dispensable for organism development but, like apoptosis, can be triggered to kill cells harboring pathogenic microbes (3). A number of studies have also reported how pathological activation of necroptotic signaling may contribute to diverse disease states, such as ischemia-reperfusion injury, atherosclerosis, and liver disease, presumably through cell death and the release of proinflammatory mediators (4).The execution of necroptosis is dependent on receptor interacting serine-threonine protein kinase 3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), and MLKL's association with, and disruption of, plasma membrane integrity (5).In the absence of caspase activit...

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mentioning

confidence: 99%

Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner

Conos

Chen

Nardo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

351

298

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“…A novel approach to eliminate HBVcore containing hepa tocytes [85] was based on findings showing that elimination of HBV is impaired by cellular inhibitor of apoptosis proteins (cIAPs), which inhibit the TNFαmediated death of HBVinfected cells [86] . This led to testing the effects of inhibitors of cIAPs, including birinapant and other Smac mimetics, on HBVinfected hepatocytes.…”

Section: Elimination Of Hbv-infected Hepatocytes By a Novel Approachmentioning

confidence: 99%

New horizon for radical cure of chronic hepatitis B virus infection

Tajiri¹,

Shimizu²

2016

WJH

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About 250 to 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and about 700000 patients per year die of HBV-related cirrhosis or hepatocellular carcinoma (HCC). Several anti-viral agents, such as interferon and nucleos(t)ide analogues (NAs), have been used to treat this disease. NAs especially have been shown to strongly suppress HBV replication, slowing the progression to cirrhosis and the development of HCC. However, reactivation of HBV replication often occurs after cessation of treatment, because NAs alone cannot completely remove covalentlyclosed circular DNA (cccDNA), the template of HBV replication, from the nuclei of hepatocytes. Anti-HBV immune responses, in conjunction with interferon-γ and tumor necrosis factor-α, were found to eliminate cccDNA, but complete eradication of cccDNA by immune response alone is difficult, as shown in patients who recover from acute HBV infection but often show long-term persistence of small amounts of HBV-DNA in the blood. Several new drugs interfering with the life cycle of HBV in hepatocytes have been developed, with drugs targeting cccDNA theoretically the most effective for radical cure of chronic HBV infection. However, the safety of these drugs should be extensively examined before application to patients, and combinations of several approaches may be necessary for radical cure of chronic HBV infection.

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“…Other strategies aim at promoting the elimination of infected hepatocytes by restoring antiviral immunity using immunomodulatory compounds (e.g. TLR7 agonists) or antigen-or DNA-based therapeutic vaccines as well as by tumor necrosis factor-mediated killing of HBV-infected hepatocytes using antagonists of cellular inhibitors of apoptosis proteins [4,5,7,[9][10][11][14][15][16]. Interestingly, given that long-term NUC treatment can restore T-cell responses in chronic hepatitis B patients, increasing antiviral T-cell responses by immunotherapeutic strategies might increase the chances of achieving control of HBV infection [17].…”

Section: Novel Therapeutic Strategies For Hbv Curementioning

confidence: 99%