The role of glycine in regulated cell death

Weinberg, Joel M.; Bienholz, Anja; Venkatachalam, Manjeri A.

doi:10.1007/s00018-016-2201-6

Cited by 71 publications

(60 citation statements)

References 261 publications

(435 reference statements)

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“…The osmoprotectant glycine delays the swelling and rupture of cells during lytic cell death, thereby slowing the release of intracellular proteins, such as lactate dehydrogenase (LDH) (31). Incubating BMDMs with increasing amounts of glycine inhibited the release of LDH following either LPS/QVD/Cp.A-induced necroptotic cell death, or ATP-induced pyroptotic cell death (Fig.…”

Section: Mlkl Oligomerization Membrane Translocation and Cell Deathmentioning

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.

380

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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Section: Mlkl Oligomerization Membrane Translocation and Cell Deathmentioning

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.

380

298

View full text Add to dashboard Cite

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“…It is therefore formally possible that a cell can repair its membrane to remove the gasdermin pore, as was recently shown during necroptosis[24]. That propidium is not simply a marker for membrane rupture and in fact enters through gasdermin pores is illustrated by the fact that propidium can enter cells after inflammasome activation even when swelling and membrane rupture are inhibited with glycine[28] (which acts through mysterious mechanisms[75,76]).…”

Section: Gasdermin D Pores Are the Effectors Of Pyroptosismentioning

confidence: 99%

Gasdermins: Effectors of Pyroptosis

Kovacs

Miao

2017

Trends in Cell Biology

1,004

662

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Pyroptosis is a form of lytic programmed cell death initiated by inflammasomes, which detect cytosolic contamination or perturbation. This drives activation of caspase-1 or caspase-11/4/5, which cleave gasdermin D, separating its N-terminal pore-forming domain (PFD) from the C-terminal repressor domain (RD). The PFD oligomerizes to form large pores in the membrane that drive swelling and membrane rupture. Gasdermin D is one of six (in humans) gasdermin family members; several other gasdermins have also been shown to form pores that cause pyroptosis after cleavage to activate their PFDs. One of these, gasdermin E, is activated by caspase-3 cleavage. We review our current understanding of pyroptosis as well as current knowledge of the gasdermin family.

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“…Highly concentrated parent reactants in the systems might be toxic to the cell; therefore, different concentrations of NR were used to treat the macrophages to determine the maximum non‐toxic concentrations, which were identified as 20 and 10 mg mL −1 for glycine–glucose and WPI–glucose system, respectively (Supporting Information 3). Macrophages were more resistant to glycine–glucose than WPI–glucose, and it was likely due to the protective effect of glycine, one of the ingredients in the medium, against cell death . These concentrations were selected for samples containing glycation products to treat macrophages.…”

Section: Resultsmentioning

confidence: 99%