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Apoptosis is a genetically regulated cell suicide programme mediated by activation of the effector caspases 3, 6 and 7. If apoptotic cells are not scavenged, they progress to a lytic and inflammatory phase called secondary necrosis. The mechanism by which this occurs is unknown. Here we show that caspase-3 cleaves the GSDMD-related protein DFNA5 after Asp270 to generate a necrotic DFNA5-N fragment that targets the plasma membrane to induce secondary necrosis/pyroptosis. Cells that express DFNA5 progress to secondary necrosis, when stimulated with apoptotic triggers such as etoposide or vesicular stomatitis virus infection, but disassemble into small apoptotic bodies when DFNA5 is deleted. Our findings identify DFNA5 as a central molecule that regulates apoptotic cell disassembly and progression to secondary necrosis, and provide a molecular mechanism for secondary necrosis. Because DFNA5-induced secondary necrosis and GSDMD-induced pyroptosis are dependent on caspase activation, we propose that they are forms of programmed necrosis. DFNA5 is related to the caspase-dependent pyroptosis inducer gasdermin D. Here the authors find that DFNA5 is cleaved by caspase 3 and show this cleavage skews cells away from apoptosis into secondary necrosis, a form of cell death characterized by membrane ballooning similar to pyroptosis.

Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that GSDME-N also permeabilizes the mitochondrial membrane, releasing cytochrome c and activating the apoptosome. Cytochrome c release and caspase-3 activation in response to intrinsic and extrinsic apoptotic stimuli are significantly reduced in GSDME-deficient cells comparing with wild type cells. GSDME deficiency also accelerates cell growth in culture and in a mouse model of melanoma. Phosphomimetic mutation of the highly conserved phosphorylatable Thr6 residue of GSDME, inhibits its pore-forming activity, thus uncovering a potential mechanism by which GSDME might be regulated. Like GSDME-N, inflammasome-generated gasdermin D-N (GSDMD-N), can also permeabilize the mitochondria linking inflammasome activation to downstream activation of the apoptosome. Collectively, our results point to a role of gasdermin proteins in targeting the mitochondria to promote cytochrome c release to augment the mitochondrial apoptotic pathway. Gasdermins mediate lytic cell death by forming pores in the plasma membrane. Here the authors show that gasdermins also permeabilize mitochondrial membrane, thereby facilitating intrinsic apoptosis pathway, downstream of apoptotic (Gasdermin E) and inflammatory (Gasdermin D) caspase activation.

TLR2 promotes NLRP3 inflammasome activation via an early MyD88-IRAK1-dependent pathway that provides a priming signal (signal 1) necessary for activation of the inflammasome by a second potassium-depleting signal (signal 2). Here we show that TLR3 binding to dsRNA promotes post-translational inflammasome activation through intermediate and late TRIF/RIPK1/FADD-dependent pathways. Both pathways require the scaffolding but not the catalytic function of caspase-8 or RIPK1. Only the late pathway requires kinase competent RIPK3 and MLKL function. Mechanistically, FADD/caspase-8 scaffolding function provides a post-translational signal 1 in the intermediate pathway, whereas in the late pathway it helps the oligomerization of RIPK3, which together with MLKL provides both signal 1 and 2 for inflammasome assembly. Cytoplasmic dsRNA activates NLRP3 independent of TRIF, RIPK1, RIPK3 or mitochondrial DRP1, but requires FADD/caspase-8 in wildtype macrophages to remove RIPK3 inhibition. Our study provides a comprehensive analysis of pathways that lead to NLRP3 inflammasome activation in response to dsRNA. Inflammasome activation requires a complex and incompletely understood network of signalling events. Here the authors characterize step-by-step contributions of TLR3, caspase-8, RIPK3 and MLKL to the activation of NLRP3 inflammasome in response to double-stranded RNA.

Apoptosis is a form of programmed cell death (PCD) that plays critical physiological roles in removing superfluous or dangerous cell populations that are unneeded or threatening to the health of the host organism. Although the molecular pathways leading to activation of the apoptotic program have been extensively studied and characterized starting in the 1970s, new evidence suggests that members of the gasdermin superfamily are novel pore-forming proteins that augment apoptosis by permeabilizing the mitochondria and participate in the final stages of the apoptotic program by inducing secondary necrosis/pyroptosis. These findings may explain outstanding questions in the field such as why certain gasdermin members sensitize cells to apoptosis, and why some apoptotic cells also show morphological features of necrosis. Furthermore, the interplay between the gasdermins and apoptosis may also explain why genetic and epigenetic alterations in these genes cause diseases and disorders like cancer and hearing loss. This review focuses on our current understanding of the function of several gasdermin superfamily members, their role in apoptosis, and how they may contribute to pathophysiological conditions.

Programmed cell death (PCD) pathways play critical physiological functions in directing our development, shaping our immune system, and maintaining our health, yet we still do not fully understand the molecules that control these processes. As PCD is vitally important for human health, it is not surprising that disruption of these signaling pathways can lead to disease. Having a more complete and detailed understanding of how these pathways are regulated can lead to the identification of novel drug targets, prognostic indicators, and biomarkers which can in turn improve disease prevention and treatment. Members of the gasdermin superfamily are just emerging as critical proteins involved in executing PCD, however their precise function and regulatory mechanisms are still not fully elucidated. One member, gasdermin E (GSDME), is transcriptionally suppressed in cancers and genetic mutations can cause progressive hearing loss. How the function of GSDME relates to these diseases, however, is currently unknown which limits our understanding of how to prevent or treat them. The work presented in this thesis sheds light on two novel functions of GSDME, both of which are involved in regulating one form of PCD called apoptosis. First, GSDME is a substrate of the cysteine protease caspase-3. When caspase-3 is activated during apoptosis, it cleaves GSDME between its N- and C-terminal domains liberating an N-terminal fragment (GSDME-N) that has an intrinsic ability to form pores in biomembranes. GSDME-N first forms pores in the mitochondria to potentiate the apoptotic pathway by augmenting the release of proapoptotic molecules into the cytosol. Later in the apoptotic program, GSDME-N also forms pores in the plasma membrane, which leads to lysis of the cell and the release of inflammatory molecules. Interestingly, these functions also appear to be conserved by other gasdermin family members. These discoveries may explain why certain forms of cancer need to suppress GSDME expression and how mutations in this gene can lead to hearing loss, and they also open new avenues for disease intervention.

Description, diagnosis and treatment. [(BNI unique abstract)]

The impact of extreme heat on crop yields is an increasingly pressing issue given anthropogenic climate warming. However, some of the physical mechanisms involved in these impacts remain unclear, impeding adaptation-relevant insight and reliable projections of future climate impacts on crops. Here, using a multiple regression model based on observational data, we show that while extreme dry heat steeply reduced U.S. corn and soy yields, humid heat extremes had insignificant impacts and even boosted yields in some areas, despite having comparably high dry-bulb temperatures as their dry heat counterparts. This result suggests that conflating dry and humid heat extremes may lead to underestimated crop yield sensitivities to extreme dry heat. Rainfall tends to precede humid but not dry heat extremes, suggesting that multivariate weather sequences play a role in these crop responses. Our results provide evidence that extreme heat in recent years primarily affected yields by inducing moisture stress, and that the conflation of humid and dry heat extremes may lead to inaccuracy in projecting crop yield responses to warming and changing humidity.

Black hole physics: A new window on the Galactic Centre Using Very Long Baseline Interferometry (VLBI) at the relatively short radio wavelength of 1.3 mm, a new intrinsic size estimate has been obtained for Sagittarius A*, the supermassive black hole candidate at the centre of the Milky Way. The resulting lower limit on the size of Sgr A* is less than the predicted size of the event horizon of the presumed black hole, suggesting that Sgr A* emissions centre not on the black hole itself but on the surrounding accretion flow. VLBI observations of the Galactic Centre at around 1.3 mm, less influenced by interstellar scattering than those made at longer wavelengths, open a new window onto black-hole physics that will become even more sensitive as new VLBI stations are built. The cores of most large galaxies are thought to harbour super massive black holes. Sagittarius A*, the compact source of radio, infrared and x-ray emission at the centre of the Milky Way, is the closest example of this phenomenon. This paper reports observations that set a limit less than the expected apparent size of the event horizon of the presumed black hole, suggesting that the bulk of Sgr A* emission may not be centred on the black hole, but arises in the surrounding accretion flow. The cores of most galaxies are thought to harbour supermassive black holes, which power galactic nuclei by converting the gravitational energy of accreting matter into radiation 1 . Sagittarius A* (Sgr A*), the compact source of radio, infrared and X-ray emission at the centre of the Milky Way, is the closest example of this phenomenon, with an estimated black hole mass that is 4,000,000 times that of the Sun 2 , 3 . A long-standing astronomical goal is to resolve structures in the innermost accretion flow surrounding Sgr A*, where strong gravitational fields will distort the appearance of radiation emitted near the black hole. Radio observations at wavelengths of 3.5 mm and 7 mm have detected intrinsic structure in Sgr A*, but the spatial resolution of observations at these wavelengths is limited by interstellar scattering 4 , 5 , 6 , 7 . Here we report observations at a wavelength of 1.3 mm that set a size of microarcseconds on the intrinsic diameter of Sgr A*. This is less than the expected apparent size of the event horizon of the presumed black hole, suggesting that the bulk of Sgr A* emission may not be centred on the black hole, but arises in the surrounding accretion flow.