scholarly journals Gasdermin D pores are dynamically regulated by local phosphoinositide circuitry

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Ana Beatriz Santa Cruz Garcia ◽  
Kevin P. Schnur ◽  
Asrar B. Malik ◽  
Gary C. H. Mo
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Pore Formation ◽  
Inflammatory Cytokine ◽  
Living Cells ◽  
Live Cell ◽  
Pore Geometry ◽  
Cytokine Release ◽  
Cell Death Program ◽  
And Control

AbstractGasdermin D forms large, ~21 nm diameter pores in the plasma membrane to drive the cell death program pyroptosis. These pores are thought to be permanently open, and the resultant osmotic imbalance is thought to be highly damaging. Yet some cells mitigate and survive pore formation, suggesting an undiscovered layer of regulation over the function of these pores. However, no methods exist to directly reveal these mechanistic details. Here, we combine optogenetic tools, live cell fluorescence biosensing, and electrophysiology to demonstrate that gasdermin pores display phosphoinositide-dependent dynamics. We quantify repeated and fast opening-closing of these pores on the tens of seconds timescale, visualize the dynamic pore geometry, and identify the signaling that controls dynamic pore activity. The identification of this circuit allows pharmacological tuning of pyroptosis and control of inflammatory cytokine release by living cells.

scholarly journals Early endosome autoantigen 1 regulates IL-1β release upon caspase-1 activation independently of gasdermin D membrane permeabilization

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Alberto Baroja-Mazo ◽  
Vincent Compan ◽  
Fátima Martín-Sánchez ◽  
Ana Tapia-Abellán ◽  
Isabelle Couillin ◽  
...  
Keyword(s):  
Pore Formation ◽  
Inflammatory Cytokine ◽  
Early Endosome ◽  
Important Process ◽  
Cytokine Release ◽  
Independent Manner ◽  
Membrane Pore ◽  
Caspase 1 ◽  
Unconventional Secretion ◽  
Secretion Pathways

AbstractUnconventional protein secretion represents an important process of the inflammatory response. The release of the pro-inflammatory cytokine interleukin (IL)-1β which burst during pyroptosis as a consequence of gasdermin D plasma membrane pore formation, can also occur through other unconventional secretion pathways dependent on caspase-1 activation. However, how caspase-1 mediates cytokine release independently of gasdermin D remains poorly understood. Here we show that following caspase-1 activation by different inflammasomes, caspase-1 cleaves early endosome autoantigen 1 (EEA1) protein at Asp127/132. Caspase-1 activation also results in the release of the endosomal EEA1 protein in a gasdermin D-independent manner. EEA1 knock-down results in adecreased release of caspase-1 and IL-1β, but the pyroptotic release of other inflammasome components and lactate dehydrogenase was not affected. This study shows how caspase-1 control the release of EEA1 and IL-1β in a pyroptotic-independent manner.

An acidic pH environment increases cell death and pro-inflammatory cytokine release in osteoblasts: The involvement of BAX Inhibitor-1

2011 ◽  
Vol 43 (9) ◽  
pp. 1305-1317 ◽  
Author(s):  
Geum-Hwa Lee ◽  
Jung-Doo Hwang ◽  
Je-Yong Choi ◽  
Hye-Jeong Park ◽  
Je-Yoel Cho ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Cytokine ◽  
Acidic Ph ◽  
Cytokine Release

scholarly journals BID and the α-bisabolol-triggered cell death program: converging on mitochondria and lysosomes

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Antonella Rigo ◽  
Isacco Ferrarini ◽  
Erika Lorenzetto ◽  
Elena Darra ◽  
Irene Liparulo ◽  
...  
Keyword(s):  
Cell Death ◽  
Blood Cells ◽  
Pore Formation ◽  
Neoplastic Cell ◽  
Autophagic Flux ◽  
Cytotoxic Effects ◽  
Sesquiterpene Alcohol ◽  
Regulated Cell Death ◽  
Cell Death Program ◽  
Microscopy Techniques

Abstractα-Bisabolol (BSB) is a plant-derived sesquiterpene alcohol able to trigger regulated cell death in transformed cells, while deprived of the general toxicity in several mouse models. Here, we investigated the involvement of lysosomal and mitochondrial compartments in the cytotoxic effects of BSB, with a specific focus on the BH3-only activator protein BID. We found that BSB particularly accumulated in cancer cell lines, displaying a higher amount of lipid rafts as compared to normal blood cells. By means of western blotting and microscopy techniques, we documented rapid BSB-induced BID translocation to lysosomes and mitochondria, both of them becoming dysfunctional. Lysosomal membranes were permeabilized, thus blocking the cytoprotective autophagic flux and provoking cathepsin B leakage into the cytosol. Multiple flow cytometry-based experiments demonstrated the loss of mitochondrial membrane potential due to pore formation across the lipid bilayer. These parallel events converged on neoplastic cell death, an outcome significantly prevented by BID knockdown. Therefore, BSB promoted BID redistribution to the cell death executioner organelles, which in turn activated anti-autophagic and proapoptotic mechanisms. This is an example of how xenohormesis can be exploited to modulate basic cellular programs in cancer.

scholarly journals Molecular and structural aspects of gasdermin family pores and insights into gasdermin-elicited programmed cell death

2021 ◽  
Author(s):  
Ayesha Zahid ◽  
Hazrat Ismail ◽  
Tengchuan Jin
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Programmed Cell Death ◽  
Pore Formation ◽  
Current Knowledge ◽  
Functional Consequences ◽  
Molecular Aspects ◽  
Pore Forming Proteins ◽  
Structural Aspects

Pyroptosis is a highly inflammatory and lytic type of programmed cell death (PCD) commenced by inflammasomes, which sense perturbations in the cytosolic environment. Recently, several ground-breaking studies have linked a family of pore-forming proteins known as gasdermins (GSDMs) to pyroptosis. The human genome encodes six GSDM proteins which have a characteristic feature of forming pores in the plasma membrane resulting in the disruption of cellular homeostasis and subsequent induction of cell death. GSDMs have an N-terminal cytotoxic domain and an auto-inhibitory C-terminal domain linked together through a flexible hinge region whose proteolytic cleavage by various enzymes releases the N-terminal fragment that can insert itself into the inner leaflet of the plasma membrane by binding to acidic lipids leading to pore formation. Emerging studies have disclosed the involvement of GSDMs in various modalities of PCD highlighting their role in diverse cellular and pathological processes. Recently, the cryo-EM structures of the GSDMA3 and GSDMD pores were resolved which have provided valuable insights into the pore formation process of GSDMs. Here, we discuss the current knowledge regarding the role of GSDMs in PCD, structural and molecular aspects of autoinhibition, and pore formation mechanism followed by a summary of functional consequences of gasdermin-induced membrane permeabilization.

Microtubule Dynamics and Organelle Transport in Reticulomyxa

1990 ◽  
Vol 48 (3) ◽  
pp. 194-195
Author(s):  
Yih-Tai Chen ◽  
Ursula Euteneuer ◽  
Ken B. Johnson ◽  
Michael P. Koonce ◽  
Manfred Schliwa
Keyword(s):  
Plasma Membrane ◽  
Light Microscopy ◽  
Cytoplasmic Dynein ◽  
Living Cells ◽  
Microtubule Dynamics ◽  
Model Systems ◽  
Organelle Transport ◽  
Biochemical Characteristics ◽  
Dependent Transport

The application of video techniques to light microscopy and the development of motility assays in reactivated or reconstituted model systems rapidly advanced our understanding of the mechanism of organelle transport and microtubule dynamics in living cells. Two microtubule-based motors have been identified that are good candidates for motors that drive organelle transport: kinesin, a plus end-directed motor, and cytoplasmic dynein, which is minus end-directed. However, the evidence that they do in fact function as organelle motors is still indirect.We are studying microtubule-dependent transport and dynamics in the giant amoeba, Reticulomyxa. This cell extends filamentous strands backed by an extensive array of microtubules along which organelles move bidirectionally at up to 20 μm/sec (Fig. 1). Following removal of the plasma membrane with a mild detergent, organelle transport can be reactivated by the addition of ATP (1). The physiological, pharmacological and biochemical characteristics show the motor to be a cytoplasmic form of dynein (2).

vitreal cells and specialized phagocytes in the chick embryo retina: A TEM and SEM study

1990 ◽  
Vol 48 (3) ◽  
pp. 330-331
Author(s):  
M.A. Cuadros ◽  
M.J. Martinez-Guerrero ◽  
A. Rios
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Acid Phosphatase ◽  
Chick Embryo ◽  
Basement Membrane ◽  
Sem Images ◽  
Intimate Contact ◽  
Cellular Processes ◽  
Sem Study ◽  
Free Cells

In the chick embryo retina (days 3-4 of incubation), coinciding with an increase in cell death, specialized phagocytes characterized by intense acid phosphatase activity have been described. In these preparations, all free cells in the vitreal humor (vitreal cells) were strongly labeled. Conventional TEM and SEM techniques were used to characterize them and attempt to determine their relationship with retinal phagocytes.Two types of vitreal cells were distinguished. The first are located at some distance from the basement membrane of the neuroepithelium, and are rounded, with numerous vacuoles and thin cytoplasmic prolongations. Images of exo- and or endocytosis were frequent; the cells showed a well-developed Golgi apparatus (Fig. 1) In SEM images, the cells was covered with short cellular processes (Fig. 3). Cells lying parallel to or alongside the basement membrane are elongated. The plasma membrane is frequently in intimate contact with the basement membrane. These cells have generally a large cytoplasmic expansion (Fig. 5).

Pentoxifylline and Oxypurinol: Potential Drugs to Prevent the “Cytokine Release (Storm) Syndrome” Caused by SARS-CoV-2?

2020 ◽  
Vol 26 (35) ◽  
pp. 4515-4521
Author(s):  
Francisco J. López-Iranzo ◽  
Ana M. López-Rodas ◽  
Luis Franco ◽  
Gerardo López-Rodas
Keyword(s):  
Lung Parenchyma ◽  
Interstitial Tissue ◽  
Cytokine Release ◽  
Phase I Clinical Trials ◽  
Infected People ◽  
Tnf Α ◽  
Transient Loss ◽  
Anti Inflammatory ◽  
And Control ◽  
Inflammatory Action

Background: COVID-19, caused by SARS-CoV-2, is a potentially lethal, rapidly-expanding pandemic and many efforts are being carried out worldwide to understand and control the disease. COVID-19 patients may display a cytokine release syndrome, which causes severe lung inflammation, leading, in many instances, to death. Objective: This paper is intended to explore the possibilities of controlling the COVID-19-associated hyperinflammation by using licensed drugs with anti-inflammatory effects. Hypothesis: We have previously described that pentoxifylline alone, or in combination with oxypurinol, reduces the systemic inflammation caused by experimentally-induced pancreatitis in rats. Pentoxifylline is an inhibitor of TNF-α production and oxypurinol inhibits xanthine oxidase. TNF-α, in turn, activates other inflammatory genes such as Nos2, Icam or IL-6, which regulate migration and infiltration of neutrophils into the pulmonary interstitial tissue, causing injury to the lung parenchyma. In acute pancreatitis, the anti-inflammatory action of pentoxifylline seems to be mediated by the prevention of the rapid and presumably transient loss of PP2A activity. This may also occur in the hyperinflammatory -cytokine releasing phase- of SARS-CoV-2 infection. Therefore, it may be hypothesized that early treatment of COVID-19 patients with pentoxifylline, alone or in combination with oxypurinol, would prevent the potentially lethal acute respiratory distress syndrome. Conclusion: Pentoxifylline and oxypurinol are licensed drugs used for diseases other than COVID-19 and, therefore, phase I clinical trials would not be necessary for the administration to SARS-CoV-2- infected people. It would be worth investigating their potential effects against the hyperinflammatory response to SARS-CoV-2 infection.

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