Active cell death, in its many forms, is a fundamental biological process. Studies over the past several decades have explored the functions and consequences of cellular demise and elucidated several ...of the key cell death pathways. Here, I pose five questions, or riddles, that might provide a guide to the next decade of cell death research. Focusing mainly on four types of active cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis) mainly in mammals, this Perspective explores the possible research directions that might answer these riddles, or at least prompt new ones.
Active cell death, in its many forms, is a fundamental biological process, and its study over the past several decades has provided key insights into the molecular processes, functions, and consequences responsible. Here, I pose five questions, or riddles, that might provide a guide to the next decade of cell death research. Focusing mainly on four types of active cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis) mainly in mammals, this Perspective explores the possible research directions that might answer these riddles, or at least prompt new ones.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Although excessive cell damage results in passive necrosis, cells can be ...triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best‐known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor‐mediated activation of programmed cell death is the aspartate‐specific cysteine protease (caspase)‐8. This review describes the role of caspase‐8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase‐8 inhibits necroptosis. The importance of caspase‐8 in the development and homeostasis and the way that dysfunctional caspase‐8 may contribute to the development of malignancies in mice and humans are also explored.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Follicular lymphoma (FL) is an indolent malignancy of germinal center B cells. Although the overall survival of FL patients has recently improved with the introduction of novel therapies, there is ...significant heterogeneity in patient outcome and a need for rationally designed therapeutic strategies that target disease biology. Next-generation sequencing studies have identified chromatin modifying gene (CMG) mutations as a hallmark of FL, highlighting epigenetic modifiers as an attractive therapeutic target in this disease. Understanding the complex roles of these mutations will be central to identifying and adaptively targeting associated vulnerabilities. Recent studies have provided insight into the functional consequences of the most frequently mutated CMGs (KMT2D, CREBBP, and EZH2) and point to a role for these events in modifying normal B-cell differentiation programs and impeding germinal center exit. However, the majority of FL tumors serially acquire multiple CMG mutations, suggesting that there is a level of cross talk or cooperation between these events that has not yet been defined. Here, I review the current state of knowledge on CMG mutations in FL, discuss their potential as therapeutic targets, and offer my perspective on unexplored areas that should be considered in the future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A set of thermodynamic models is presented that, for the first time, allows partial melting equilibria to be calculated for metabasic rocks. The models consist of new activity–composition relations ...combined with end‐member thermodynamic properties from the Holland & Powell dataset, version 6. They allow for forward modelling in the system Na2O–CaO–K2O–FeO–MgO–Al2O3–SiO2–H2O–TiO2–Fe2O3. In particular, new activity–composition relations are presented for silicate melt of broadly trondhjemitic–tonalitic composition, and for augitic clinopyroxene with Si–Al mixing on the tetrahedral sites, while existing activity–composition relations for hornblende are extended to include K2O and TiO2. Calibration of the activity–composition relations was carried out with the aim of reproducing major experimental phase‐in/phase‐out boundaries that define the amphibolite–granulite transition, across a range of bulk compositions, at ≤13 kbar.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The health of metazoan organisms requires an effective response to organellar and cellular damage either by repair of such damage and/or by elimination of the damaged parts of the cells or the ...damaged cell in its entirety. Here, we consider the progress that has been made in the last few decades in determining the fates of damaged organelles and damaged cells through discrete, but genetically overlapping, pathways involving the selective autophagy and cell death machinery. We further discuss the ways in which the autophagy machinery may impact the clearance and consequences of dying cells for host physiology. Failure in the proper removal of damaged organelles and/or damaged cells by selective autophagy and cell death processes is likely to contribute to developmental abnormalities, cancer, aging, inflammation, and other diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Chloroplast genomes have retained a core set of genes from their cyanobacterial ancestor, most of them required for the light reactions of photosynthesis or functions connected with ...transcription and translation. Other genes have been transferred to the nucleus or were lost in a lineage‐specific manner. The genomes are distinguished by the selection of genes retained, whether or not transcripts are edited, presence/absence of introns and small repeats and their physical organization. Plants and green algae have kept fewer plastid genes than either the red algae or the chromistan algae, which obtained their plastids from red algae by secondary endosymbiosis. Photosynthetic dinoflagellates have the fewest (fewer than 20), but still grow photoautotrophically. All chloroplast genomes map as a circle, but there have been extensive rearrangements of gene order even between related species. Genome sizes vary much more than gene content, depending on the extent of gene duplication and small repeats and the size of intergenic spacers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The c-Myc HLH-bZIP protein has been implicated in physiological or pathological growth, proliferation, apoptosis, metabolism, and differentiation at the cellular, tissue, or organismal levels via ...regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc’s targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated, the transcriptomes and the genome-wide distributions of Myc, RNA polymerase II, and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity, but is a nonlinear amplifier of expression, acting universally at active genes, except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Metabolic control of cell death Green, Douglas R.; Galluzzi, Lorenzo; Kroemer, Guido
Science,
09/2014, Volume:
345, Issue:
6203
Journal Article
Peer reviewed
Open access
Beyond their contribution to basic metabolism, the major cellular organelles, in particular mitochondria, can determine whether cells respond to stress in an adaptive or suicidal manner. Thus, ...mitochondria can continuously adapt their shape to changing bioenergetic demands as they are subjected to quality control by autophagy, or they can undergo a lethal permeabilization process that initiates apoptosis. Along similar lines, multiple proteins involved in metabolic circuitries, including oxidative phosphorylation and transport of metabolites across membranes, may participate in the regulated or catastrophic dismantling of organelles. Many factors that were initially characterized as cell death regulators are now known to physically or functionally interact with metabolic enzymes. Thus, several metabolic cues regulate the propensity of cells to activate self-destructive programs, in part by acting on nutrient sensors. This suggests the existence of “metabolic checkpoints” that dictate cell fate in response to metabolic fluctuations. Here, we discuss recent insights into the intersection between metabolism and cell death regulation that have major implications for the comprehension and manipulation of unwarranted cell loss.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Classically, canonical autophagy has been considered a survival mechanism initiated in response to nutrient insufficiency. We now understand that autophagy functions in multiple scenarios where it is ...necessary to maintain homeostasis. Recent evidence has established that a variety of non-canonical functions for autophagy proteins are mechanistically and functionally distinct from autophagy. LC3-associated phagocytosis (LAP) is one such novel function for autophagy proteins and is a contributor to immune regulation and inflammatory responses across various cell and tissue types. Characterized by the conjugation of LC3 family proteins to phagosome membranes, LAP uses a portion of the canonical autophagy machinery, following ligation of surface receptors that recognize a variety of cargos including pathogens, dying cells, soluble ligands and protein aggregates. However, instead of affecting canonical autophagy, manipulation of the LAP pathway
alters immune activation and inflammatory responses. In this Cell Science at a Glance article and the accompanying poster, we detail the divergence of this distinctive mechanism from that of canonical autophagy by comparing and contrasting shared and unique components of each pathway.
Receptor Interacting Protein Kinase-1 (RIPK1), a key player in inflammation and cell death, assumes opposite functions depending on the cellular context and its posttranslational modifications. ...Genetic evidence supported by biochemical and cellular biology approaches sheds light on the circumstances in which RIPK1 promotes or inhibits these processes.
Receptor Interacting Protein Kinase-1 (RIPK1), a key player in inflammation and cell death, assumes opposite functions depending on the cellular context and its posttranslational modifications. Genetic evidence supported by biochemical and cellular biology approaches sheds light on the circumstances in which RIPK1 promotes or inhibits these processes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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