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Nature Cell Biology Mar 2023SLC7A11-mediated cystine uptake suppresses ferroptosis yet promotes cell death under glucose starvation; the nature of the latter cell death remains unknown. Here we...
SLC7A11-mediated cystine uptake suppresses ferroptosis yet promotes cell death under glucose starvation; the nature of the latter cell death remains unknown. Here we show that aberrant accumulation of intracellular disulfides in SLC7A11 cells under glucose starvation induces a previously uncharacterized form of cell death distinct from apoptosis and ferroptosis. We term this cell death disulfidptosis. Chemical proteomics and cell biological analyses showed that glucose starvation in SLC7A11 cells induces aberrant disulfide bonds in actin cytoskeleton proteins and F-actin collapse in a SLC7A11-dependent manner. CRISPR screens and functional studies revealed that inactivation of the WAVE regulatory complex (which promotes actin polymerization and lamellipodia formation) suppresses disulfidptosis, whereas constitutive activation of Rac promotes disulfidptosis. We further show that glucose transporter inhibitors induce disulfidptosis in SLC7A11 cancer cells and suppress SLC7A11 tumour growth. Our results reveal that the susceptibility of the actin cytoskeleton to disulfide stress mediates disulfidptosis and suggest a therapeutic strategy to target disulfidptosis in cancer treatment.
Topics: Humans; Disulfides; Neoplasms; Apoptosis; Actin Cytoskeleton; Glucose
PubMed: 36747082
DOI: 10.1038/s41556-023-01091-2 -
Cells & Development Dec 2021Macropinocytosis is a form of endocytosis performed by ruffles and cups of the plasma membrane. These close to entrap droplets of medium into micron-sized vesicles,... (Review)
Review
Macropinocytosis is a form of endocytosis performed by ruffles and cups of the plasma membrane. These close to entrap droplets of medium into micron-sized vesicles, which are trafficked through the endocytic system, their contents digested and useful products absorbed. Macropinocytosis is constitutive in certain immune cells and stimulated in many other cells by growth factors. It occurs across the animal kingdom and in amoebae, implying a deep evolutionary history. Its scientific history goes back 100 years, but increasingly work is focused on its medical importance in the immune system, cancer cell feeding, and as a backdoor into cells for viruses and drugs. Macropinocytosis is driven by the actin cytoskeleton whose dynamics can be appreciated with lattice light sheet microscopy: this reveals a surprising variety of routes for forming macropinosomes. In Dictyostelium amoebae, macropinocytic cups are organized around domains of PIP3 and active Ras and Rac in the plasma membrane. These attract activators of the Arp2/3 complex to their periphery, creating rings of actin polymerization that shape the cups. The size of PIP3 domains is controlled by RasGAPs, such as NF1, and the lipid phosphatase, PTEN. It is likely that domain dynamics determine the shape, evolution and closing of macropinocytic structures.
Topics: Actin Cytoskeleton; Amoeba; Animals; Biology; Dictyostelium; Endocytosis; Pinocytosis
PubMed: 34175511
DOI: 10.1016/j.cdev.2021.203713 -
Journal of Experimental & Clinical... May 2023Disulfidptosis, a new form of cell death triggered by disulfide stress, is characterized by the collapse of cytoskeleton proteins and F-actin due to the intracellular...
Disulfidptosis, a new form of cell death triggered by disulfide stress, is characterized by the collapse of cytoskeleton proteins and F-actin due to the intracellular accumulation of disulfides. This discovery will eventually aid in the development of therapeutic strategies against cancer.
Topics: Humans; Apoptosis; Actins; Actin Cytoskeleton; Cell Death; Cytoskeletal Proteins
PubMed: 37259067
DOI: 10.1186/s13046-023-02712-2 -
Current Biology : CB May 2021Actin is one of the most abundant proteins in eukaryotes. Discovered in muscle and described as far back as 1887, actin was first purified in 1942. It plays myriad roles...
Actin is one of the most abundant proteins in eukaryotes. Discovered in muscle and described as far back as 1887, actin was first purified in 1942. It plays myriad roles in essentially every eukaryotic cell. Actin is central to development, muscle contraction, and cell motility, and it also functions in the nucleus, to name a spectrum of examples. The flexibility of actin function stems from two factors: firstly, it is dynamic, transitioning between monomer and filament, and, secondly, there are hundreds of actin-binding proteins that build and organize specific actin-based structures. Of prime importance are actin nucleators - proteins that stimulate de novo formation of actin filaments. There are three known classes of actin nucleators: the Arp2/3 complex, formins, and tandem WASP homology 2 (WH2) nucleators. Each class nucleates by a distinct mechanism that contributes to the organization of the larger structure being built. Evidence shows that the Arp2/3 complex produces branched actin filaments, remaining bound at the branch point, while formins create linear actin filaments, remaining bound at the growing end. Here, we focus on the formin family of actin nucleators.
Topics: Actin Cytoskeleton; Actin-Related Protein 2-3 Complex; Actins; Formins; Microfilament Proteins
PubMed: 34033783
DOI: 10.1016/j.cub.2021.02.047 -
Nature Nov 2022The dynamic turnover of actin filaments (F-actin) controls cellular motility in eukaryotes and is coupled to changes in the F-actin nucleotide state. It remains unclear...
The dynamic turnover of actin filaments (F-actin) controls cellular motility in eukaryotes and is coupled to changes in the F-actin nucleotide state. It remains unclear how F-actin hydrolyses ATP and subsequently undergoes subtle conformational rearrangements that ultimately lead to filament depolymerization by actin-binding proteins. Here we present cryo-electron microscopy structures of F-actin in all nucleotide states, polymerized in the presence of Mg or Ca at approximately 2.2 Å resolution. The structures show that actin polymerization induces the relocation of water molecules in the nucleotide-binding pocket, activating one of them for the nucleophilic attack of ATP. Unexpectedly, the back door for the subsequent release of inorganic phosphate (P) is closed in all structures, indicating that P release occurs transiently. The small changes in the nucleotide-binding pocket after ATP hydrolysis and P release are sensed by a key amino acid, amplified and transmitted to the filament periphery. Furthermore, differences in the positions of water molecules in the nucleotide-binding pocket explain why Ca-actin shows slower polymerization rates than Mg-actin. Our work elucidates the solvent-driven rearrangements that govern actin filament assembly and aging and lays the foundation for the rational design of drugs and small molecules for imaging and therapeutic applications.
Topics: Actin Cytoskeleton; Actins; Adenosine Triphosphate; Cryoelectron Microscopy; Hydrolysis; Nucleotides; Water; Aging; Magnesium; Calcium; Amino Acids; Phosphates
PubMed: 36289337
DOI: 10.1038/s41586-022-05241-8 -
Current Biology : CB May 2021Cell morphology, architecture and dynamics primarily rely on intracellular cytoskeletal networks, which in metazoans are mainly composed of actin microfilaments,...
Cell morphology, architecture and dynamics primarily rely on intracellular cytoskeletal networks, which in metazoans are mainly composed of actin microfilaments, microtubules and intermediate filaments (IFs). The diameter size of 10 nm - intermediate between the diameters of actin microfilaments and microtubules - initially gave IFs their name. However, the structure, dynamics, mechanical properties and functions of IFs are not intermediate but set them apart from actin and microtubules. Because of their nucleotide-independent assembly, the lack of intrinsic polarity, their relative stability and their complex composition, IFs had long been overlooked by cell biologists. Now, the numerous human diseases identified to be associated with IF gene mutations and the accumulating evidence of IF functions in cell and tissue integrity explain the growing attention that is being given to the structural characteristics, dynamics and functions of these filaments. In this Primer, we highlight the growing evidence that has revealed a role for IFs as a key element of the cytoskeleton, providing versatile, tunable, cell-type-specific filamentous networks with unique cytoplasmic and nuclear functions.
Topics: Actin Cytoskeleton; Actins; Cytoskeleton; Humans; Intermediate Filaments; Microtubules
PubMed: 34033784
DOI: 10.1016/j.cub.2021.04.011 -
Current Biology : CB May 2021Arit Ghosh and Velia Fowler introduce the structural features and functions of tropomodulins - actin-binding proteins that cap the slow-growing (pointed) ends of actin...
Arit Ghosh and Velia Fowler introduce the structural features and functions of tropomodulins - actin-binding proteins that cap the slow-growing (pointed) ends of actin filaments.
Topics: Actin Cytoskeleton; Actins; Microfilament Proteins; Tropomodulin
PubMed: 34033779
DOI: 10.1016/j.cub.2021.01.055 -
Current Biology : CB May 2021Robert Insall introduces the cytoskeleton special issue and summarises some recent changes in our view of actin function and regulation.
Robert Insall introduces the cytoskeleton special issue and summarises some recent changes in our view of actin function and regulation.
Topics: Actin Cytoskeleton; Actins; Cytoskeleton; Microtubules
PubMed: 34033777
DOI: 10.1016/j.cub.2021.04.013 -
Nature Mar 2021Symmetric cell division requires the even partitioning of genetic information and cytoplasmic contents between daughter cells. Whereas the mechanisms coordinating the...
Symmetric cell division requires the even partitioning of genetic information and cytoplasmic contents between daughter cells. Whereas the mechanisms coordinating the segregation of the genome are well known, the processes that ensure organelle segregation between daughter cells remain less well understood. Here we identify multiple actin assemblies with distinct but complementary roles in mitochondrial organization and inheritance in mitosis. First, we find a dense meshwork of subcortical actin cables assembled throughout the mitotic cytoplasm. This network scaffolds the endoplasmic reticulum and organizes three-dimensional mitochondrial positioning to ensure the equal segregation of mitochondrial mass at cytokinesis. Second, we identify a dynamic wave of actin filaments reversibly assembling on the surface of mitochondria during mitosis. Mitochondria sampled by this wave are enveloped within actin clouds that can spontaneously break symmetry to form elongated comet tails. Mitochondrial comet tails promote randomly directed bursts of movement that shuffle mitochondrial position within the mother cell to randomize inheritance of healthy and damaged mitochondria between daughter cells. Thus, parallel mechanisms mediated by the actin cytoskeleton ensure both equal and random inheritance of mitochondria in symmetrically dividing cells.
Topics: Actin Cytoskeleton; Actins; Animals; Cell Division; Cell Line; Cytokinesis; Endoplasmic Reticulum; Hippocampus; Humans; Mitochondria; Mitosis; Neurons; Rats
PubMed: 33658713
DOI: 10.1038/s41586-021-03309-5 -
Biomedicine & Pharmacotherapy =... Dec 2022Renal injury and the development of albuminuria are tightly connected with the loss of podocytes. Podocyte damages cause proteinuric renal diseases since podocyte foot... (Review)
Review
Renal injury and the development of albuminuria are tightly connected with the loss of podocytes. Podocyte damages cause proteinuric renal diseases since podocyte foot processes (FP) and their interposed slit diaphragms (SD) are the final barriers against protein loss. Podocyte effacement and the resultant deterioration of podocyte SD integrity that involve the active rearrangement of the podocyte actin cytoskeleton is a chief mechanism of proteinuric kidney diseases. The progress of these injuries can eventually lead to cell detachment and death. Due to the prominence of the actin cytoskeleton in maintaining glomerular filtration, the assessment of the molecular design and regulation of actin is a central target of podocyte research. In the current review, a comprehensive summary of the actin cytoskeleton, its constituents, and regulatory signaling pathways has been provided. Since actin-regulated cell plasticity is a crucial feature of normal podocyte function, and deteriorations in its dynamics seem to directly affect podocyte morphology and glomerular permeability, this review discusses cascades that regulate actin polymerization in podocytes.
Topics: Actins; Actin Cytoskeleton; Podocytes; Kidney Glomerulus; Intercellular Junctions
PubMed: 36411613
DOI: 10.1016/j.biopha.2022.113920