scholarly journals Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair

2010 ◽  
Vol 189 (6) ◽  
pp. 1027-1038 ◽  
Author(s):  
Christina Tam ◽  
Vincent Idone ◽  
Cecilia Devlin ◽  
Maria Cecilia Fernandes ◽  
Andrew Flannery ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Lysosomal Enzyme ◽  
Membrane Integrity ◽  
Acid Sphingomyelinase ◽  
Membrane Repair ◽  
Membrane Injury ◽  
Cellular Survival ◽  
Plasma Membrane Repair ◽  
Membrane Resealing ◽  
Niemann Pick

Rapid plasma membrane resealing is essential for cellular survival. Earlier studies showed that plasma membrane repair requires Ca2+-dependent exocytosis of lysosomes and a rapid form of endocytosis that removes membrane lesions. However, the functional relationship between lysosomal exocytosis and the rapid endocytosis that follows membrane injury is unknown. In this study, we show that the lysosomal enzyme acid sphingomyelinase (ASM) is released extracellularly when cells are wounded in the presence of Ca2+. ASM-deficient cells, including human cells from Niemann-Pick type A (NPA) patients, undergo lysosomal exocytosis after wounding but are defective in injury-dependent endocytosis and plasma membrane repair. Exogenously added recombinant human ASM restores endocytosis and resealing in ASM-depleted cells, suggesting that conversion of plasma membrane sphingomyelin to ceramide by this lysosomal enzyme promotes lesion internalization. These findings reveal a molecular mechanism for restoration of plasma membrane integrity through exocytosis of lysosomes and identify defective plasma membrane repair as a possible component of the severe pathology observed in NPA patients.

scholarly journals Trypanosoma cruzi subverts the sphingomyelinase-mediated plasma membrane repair pathway for cell invasion

2011 ◽  
Vol 208 (5) ◽  
pp. 909-921 ◽  
Author(s):  
Maria Cecilia Fernandes ◽  
Mauro Cortez ◽  
Andrew R. Flannery ◽  
Christina Tam ◽  
Renato A. Mortara ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Trypanosoma Cruzi ◽  
Host Cell ◽  
Cell Invasion ◽  
Acid Sphingomyelinase ◽  
Host Cells ◽  
Cell Contact ◽  
Membrane Repair ◽  
Membrane Injury ◽  
Plasma Membrane Repair

Upon host cell contact, the protozoan parasite Trypanosoma cruzi triggers cytosolic Ca2+ transients that induce exocytosis of lysosomes, a process required for cell invasion. However, the exact mechanism by which lysosomal exocytosis mediates T. cruzi internalization remains unclear. We show that host cell entry by T. cruzi mimics a process of plasma membrane injury and repair that involves Ca2+-dependent exocytosis of lysosomes, delivery of acid sphingomyelinase (ASM) to the outer leaflet of the plasma membrane, and a rapid form of endocytosis that internalizes membrane lesions. Host cells incubated with T. cruzi trypomastigotes are transiently wounded, show increased levels of endocytosis, and become more susceptible to infection when injured with pore-forming toxins. Inhibition or depletion of lysosomal ASM, which blocks plasma membrane repair, markedly reduces the susceptibility of host cells to T. cruzi invasion. Notably, extracellular addition of sphingomyelinase stimulates host cell endocytosis, enhances T. cruzi invasion, and restores normal invasion levels in ASM-depleted cells. Ceramide, the product of sphingomyelin hydrolysis, is detected in newly formed parasitophorous vacuoles containing trypomastigotes but not in the few parasite-containing vacuoles formed in ASM-depleted cells. Thus, T. cruzi subverts the ASM-dependent ceramide-enriched endosomes that function in plasma membrane repair to infect host cells.

scholarly journals Mitochondrial fragmentation enables localized signaling required for cell repair

2020 ◽  
Vol 219 (5) ◽  
Author(s):  
Adam Horn ◽  
Shreya Raavicharla ◽  
Sonna Shah ◽  
Dan Cox ◽  
Jyoti K. Jaiswal
Keyword(s):  
Plasma Membrane ◽  
Calcium Influx ◽  
Cell Damage ◽  
Mitochondrial Fission ◽  
Adaptor Protein ◽  
Mitochondrial Fragmentation ◽  
Membrane Repair ◽  
Membrane Injury ◽  
Mitochondrial Signaling ◽  
Plasma Membrane Repair

Plasma membrane injury can cause lethal influx of calcium, but cells survive by mounting a polarized repair response targeted to the wound site. Mitochondrial signaling within seconds after injury enables this response. However, as mitochondria are distributed throughout the cell in an interconnected network, it is unclear how they generate a spatially restricted signal to repair the plasma membrane wound. Here we show that calcium influx and Drp1-mediated, rapid mitochondrial fission at the injury site help polarize the repair response. Fission of injury-proximal mitochondria allows for greater amplitude and duration of calcium increase in these mitochondria, allowing them to generate local redox signaling required for plasma membrane repair. Drp1 knockout cells and patient cells lacking the Drp1 adaptor protein MiD49 fail to undergo injury-triggered mitochondrial fission, preventing polarized mitochondrial calcium increase and plasma membrane repair. Although mitochondrial fission is considered to be an indicator of cell damage and death, our findings identify that mitochondrial fission generates localized signaling required for cell survival.

scholarly journals Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth

2021 ◽  
Author(s):  
Suprit Gupta ◽  
Julian Yano ◽  
Htet Htwe Htwe ◽  
Hijai R. Shin ◽  
Zeynep Cakir ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Plasma Membrane ◽  
Membrane Damage ◽  
Membrane Integrity ◽  
Human Pancreatic Cancer ◽  
Cancer Growth ◽  
Membrane Repair ◽  
Pancreatic Cancer Cells ◽  
Plasma Membrane Repair

AbstractLysosomes must maintain integrity of their limiting membrane to ensure efficient fusion with incoming organelles and degradation of substrates within their lumen. Pancreatic cancer cells upregulate lysosomal biogenesis to enhance nutrient recycling and stress resistance, but whether dedicated programs for maintaining lysosomal membrane integrity facilitate pancreatic cancer growth is unknown. Using proteomic-based organelle profiling, we identify the Ferlin family plasma membrane repair factor, Myoferlin, as selectively and highly enriched on the membrane of pancreatic cancer lysosomes. Mechanistically, lysosome localization of Myoferlin is necessary and sufficient for maintenance of lysosome health and provides an early-acting protective system against membrane damage that is independent from the endosomal sorting complex required for transport (ESCRT)-mediated repair network. Myoferlin is upregulated in human pancreatic cancer, predicts poor survival, and its ablation severely impairs lysosome function and tumour growth in vivo. Thus, retargeting of plasma membrane repair factors enhances pro-oncogenic activities of the lysosome.

scholarly journals Impaired membrane resealing and autoimmune myositis in synaptotagmin VII–deficient mice

2003 ◽  
Vol 162 (4) ◽  
pp. 543-549 ◽  
Author(s):  
Sabyasachi Chakrabarti ◽  
Koichi S. Kobayashi ◽  
Richard A. Flavell ◽  
Carolyn B. Marks ◽  
Katsuya Miyake ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Inflammatory Myopathy ◽  
Response Characteristic ◽  
Membrane Repair ◽  
Progressive Muscle Weakness ◽  
Autoimmune Myositis ◽  
Mouse Tissues ◽  
Plasma Membrane Repair ◽  
Membrane Resealing ◽  
Deficient Mice

Members of the synaptotagmin family have been proposed to function as Ca2+ sensors in membrane fusion. Syt VII is a ubiquitously expressed synaptotagmin previously implicated in plasma membrane repair and Trypanosoma cruzi invasion, events which are mediated by the Ca2+-regulated exocytosis of lysosomes. Here, we show that embryonic fibroblasts from Syt VII–deficient mice are less susceptible to trypanosome invasion, and defective in lysosomal exocytosis and resealing after wounding. Examination of mutant mouse tissues revealed extensive fibrosis in the skin and skeletal muscle. Inflammatory myopathy, with muscle fiber invasion by leukocytes and endomysial collagen deposition, was associated with elevated creatine kinase release and progressive muscle weakness. Interestingly, similar to what is observed in human polymyositis/dermatomyositis, the mice developed a strong antinuclear antibody response, characteristic of autoimmune disorders. Thus, defective plasma membrane repair in tissues under mechanical stress may favor the development of inflammatory autoimmune disease.

scholarly journals Perforin activates clathrin- and dynamin-dependent endocytosis, which is required for plasma membrane repair and delivery of granzyme B for granzyme-mediated apoptosis

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1582-1593 ◽  
Author(s):  
Jerome Thiery ◽  
Dennis Keefe ◽  
Saviz Saffarian ◽  
Denis Martinvalet ◽  
Michael Walch ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cytotoxic T Lymphocytes ◽  
Granzyme B ◽  
Membrane Integrity ◽  
Effector Proteins ◽  
Target Cells ◽  
Membrane Repair ◽  
Early Endosomes ◽  
Plasma Membrane Repair ◽  
Immunologic Synapse

Abstract Cytotoxic T lymphocytes and natural killer cells destroy target cells via the polarized exocytosis of lytic effector proteins, perforin and granzymes, into the immunologic synapse. How these molecules enter target cells is not fully understood. It is debated whether granzymes enter via perforin pores formed at the plasma membrane or whether perforin and granzymes are first endocytosed and granzymes are then released from endosomes into the cytoplasm. We previously showed that perforin disruption of the plasma membrane induces a transient Ca2+ flux into the target cell that triggers a wounded membrane repair response in which lysosomes and endosomes donate their membranes to reseal the damaged membrane. Here we show that perforin activates clathrin- and dynamin-dependent endocytosis, which removes perforin and granzymes from the plasma membrane to early endosomes, preserving outer membrane integrity. Inhibiting clathrin- or dynamin-dependent endocytosis shifts death by perforin and granzyme B from apoptosis to necrosis. Thus by activating endocytosis to preserve membrane integrity, perforin facilitates granzyme uptake and avoids the proinflammatory necrotic death of a membrane-damaged cell.

Annexins Bend Wound Edges during Plasma Membrane Repair

2020 ◽  
Vol 27 (22) ◽  
pp. 3600-3610 ◽  
Author(s):  
Adam Cohen Simonsen ◽  
Theresa Louise Boye ◽  
Jesper Nylandsted
Keyword(s):  
Plasma Membrane ◽  
Cancer Cells ◽  
Membrane Curvature ◽  
Eukaryotic Cells ◽  
Repair System ◽  
Membrane Repair ◽  
Membrane Injury ◽  
Anionic Phospholipids ◽  
Annexin A4 ◽  
Plasma Membrane Repair

The plasma membrane of eukaryotic cells defines the boundary to the extracellular environment and, thus provides essential protection from the surroundings. Consequently, disruptions to the cell membrane triggered by excessive mechanical or biochemical stresses pose fatal threats to cells, which they need to cope with to survive. Eukaryotic cells cope with these threats by activating their plasma membrane repair system, which is shared by other cellular functions, and includes mechanisms to remove damaged membrane by internalization (endocytosis), shedding, reorganization of cytoskeleton and membrane fusion events to reseal the membrane. Members of the annexin protein family, which are characterized by their Ca2+-dependent binding to anionic phospholipids, are important regulators of plasma membrane repair. Recent studies based on cellular and biophysical membrane models show that they have more distinct functions in the repair response than previously assumed by regulating membrane curvature and excision of damaged membrane. In cells, plasma membrane injury and flux of Ca2+ ions into the cytoplasm trigger recruitment of annexins including annexin A4 and A6 to the membrane wound edges. Here, they induce curvature and constriction force, which help pull the wound edges together for eventual fusion. Cancer cells are dependent on efficient plasma membrane repair to counteract frequent stress-induced membrane injuries, which opens novel avenues to target cancer cells through their membrane repair system. Here, we discuss mechanisms of single cell wound healing implicating annexin proteins and membrane curvature.

scholarly journals Interdisciplinary Synergy to Reveal Mechanisms of Annexin-Mediated Plasma Membrane Shaping and Repair

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1029 ◽  
Author(s):  
Poul Martin Bendix ◽  
Adam Cohen Simonsen ◽  
Christoffer D. Florentsen ◽  
Swantje Christin Häger ◽  
Anna Mularski ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Biology ◽  
Membrane Damage ◽  
Membrane Integrity ◽  
Interdisciplinary Approach ◽  
Membrane Repair ◽  
Cell Membrane Integrity ◽  
Curvature Sensing ◽  
Plasma Membrane Repair ◽  
Curved Membranes

The plasma membrane surrounds every single cell and essentially shapes cell life by separating the interior from the external environment. Thus, maintenance of cell membrane integrity is essential to prevent death caused by disruption of the plasma membrane. To counteract plasma membrane injuries, eukaryotic cells have developed efficient repair tools that depend on Ca2+- and phospholipid-binding annexin proteins. Upon membrane damage, annexin family members are activated by a Ca2+ influx, enabling them to quickly bind at the damaged membrane and facilitate wound healing. Our recent studies, based on interdisciplinary research synergy across molecular cell biology, experimental membrane physics, and computational simulations show that annexins have additional biophysical functions in the repair response besides enabling membrane fusion. Annexins possess different membrane-shaping properties, allowing for a tailored response that involves rapid bending, constriction, and fusion of membrane edges for resealing. Moreover, some annexins have high affinity for highly curved membranes that appear at free edges near rupture sites, a property that might accelerate their recruitment for rapid repair. Here, we discuss the mechanisms of annexin-mediated membrane shaping and curvature sensing in the light of our interdisciplinary approach to study plasma membrane repair.

scholarly journals Plasma Membrane Repair: A Central Process for Maintaining Cellular Homeostasis

Physiology ◽  
2015 ◽  
Vol 30 (6) ◽  
pp. 438-448 ◽  
Author(s):  
Alisa D. Blazek ◽  
Brian J. Paleo ◽  
Noah Weisleder
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Cell Membrane ◽  
Cellular Response ◽  
Cellular Functions ◽  
Membrane Repair ◽  
Central Process ◽  
Plasma Membrane Repair ◽  
Molecular Machinery ◽  
Membrane Resealing

Plasma membrane repair is a conserved cellular response mediating active resealing of membrane disruptions to maintain homeostasis and prevent cell death and progression of multiple diseases. Cell membrane repair repurposes mechanisms from various cellular functions, including vesicle trafficking, exocytosis, and endocytosis, to mend the broken membrane. Recent studies increased our understanding of membrane repair by establishing the molecular machinery contributing to membrane resealing. Here, we review some of the key proteins linked to cell membrane repair.

scholarly journals Caveolae internalization repairs wounded cells and muscle fibers

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Matthias Corrotte ◽  
Patricia E Almeida ◽  
Christina Tam ◽  
Thiago Castro-Gomes ◽  
Maria Cecilia Fernandes ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Muscle Fibers ◽  
Mechanistic Explanation ◽  
Cell Types ◽  
Underlying Mechanism ◽  
Acid Sphingomyelinase ◽  
Muscle Pathology ◽  
Dystrophic Muscle ◽  
Cellular Survival ◽  
Membrane Resealing

Rapid repair of plasma membrane wounds is critical for cellular survival. Muscle fibers are particularly susceptible to injury, and defective sarcolemma resealing causes muscular dystrophy. Caveolae accumulate in dystrophic muscle fibers and caveolin and cavin mutations cause muscle pathology, but the underlying mechanism is unknown. Here we show that muscle fibers and other cell types repair membrane wounds by a mechanism involving Ca2+-triggered exocytosis of lysosomes, release of acid sphingomyelinase, and rapid lesion removal by caveolar endocytosis. Wounding or exposure to sphingomyelinase triggered endocytosis and intracellular accumulation of caveolar vesicles, which gradually merged into larger compartments. The pore-forming toxin SLO was directly visualized entering cells within caveolar vesicles, and depletion of caveolin inhibited plasma membrane resealing. Our findings directly link lesion removal by caveolar endocytosis to the maintenance of plasma membrane and muscle fiber integrity, providing a mechanistic explanation for the muscle pathology associated with mutations in caveolae proteins.

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