scholarly journals Naturally Occurring Shorter and Tumor-associated Mutant RNF167 Variants Facilitates Lysosomal Exocytosis and Plasma Membrane Resealing

2019 ◽  
Author(s):  
Sreeja V. Nair ◽  
Nikhil Dev Narendradev ◽  
Rithwik P. Nambiar ◽  
Rakesh Kumar ◽  
Srinivasa M. Srinivasula
Keyword(s):  
Plasma Membrane ◽  
Short Version ◽  
Membrane Repair ◽  
Primary Tumors ◽  
Upstream Regulator ◽  
Naturally Occurring ◽  
Natural Variants ◽  
Functional Features ◽  
Membrane Resealing ◽  
Isoform B

AbstractLysosomal exocytosis and resealing of damaged plasma membrane play critical roles in physiological and pathological processes, including, restoration of cellular homeostasis and tumor invasion. However, to-date, only a few regulatory molecules of these biological processes have been identified. Moreover, no mutations in any of the known regulators of lysosomal exocytosis in primary tumors of patients have been characterized. Here we demonstrate that RNF167, a lysosomal associated ubiquitin ligase, negatively regulates lysosomal exocytosis by inducing perinuclear clustering of lysosomes. Importantly, we also characterized a set of novel natural mutations in RNF167, which are commonly found in diverse tumor types. We found that RNF167-K97N mutant, unlike the wild-type, localizes in the cytoplasm and does not promote perinuclear lysosomal clustering and that cells expressing RNF167-K97N exhibit dispersed lysosomes, increased exocytosis, and enhanced plasma membrane repair. Interestingly, these functional features of RNF167-K97N were shared with a naturally occurring short version of RNF167, i.e. isoform b. In brief, the results presented here reveal a novel role of RNF167 as well as its natural variants, RNF167-K97N and RNF167-b as an upstream regulator of lysosomal exocytosis and plasma membrane resealing which might play an important role in organelle dynamics or tumor progression or both.

scholarly journals Naturally occurring and tumor-associated variants of RNF167 promote lysosomal exocytosis and plasma membrane resealing

2020 ◽  
Vol 133 (11) ◽  
pp. jcs239335 ◽  
Author(s):  
Sreeja V. Nair ◽  
Nikhil Dev Narendradev ◽  
Rithwik P. Nambiar ◽  
Rakesh Kumar ◽  
Srinivasa M. Srinivasula
Keyword(s):  
Plasma Membrane ◽  
Naturally Occurring ◽  
Membrane Resealing

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 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 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.

The mechanism of cell membrane repair

Zygote ◽  
1999 ◽  
Vol 8 (S1) ◽  
pp. S31-S32 ◽  
Author(s):  
Tatsuru Togo ◽  
Janet M. Alderton ◽  
Richard A. Steinhardt
Keyword(s):  
Plasma Membrane ◽  
Sea Urchin ◽  
Plasma Membranes ◽  
Membrane Repair ◽  
Sea Urchin Egg ◽  
Calmodulin Kinase ◽  
Intracellular Ca ◽  
Plasma Membrane Repair ◽  
Botulinum Neurotoxins ◽  
Membrane Resealing

Disruption of plasma membranes is a widespread, common and normal event that occurs in many mechanically challenged tissues (McNeil & Steinhardt, 1997). After injury to the plasma membrane, rapid resealing of the membrane occurs with little loss of intracellular contents.Analysis of plasma membrane repair in the sea urchin egg and early embryos revealed a new model of the mechanism for plasma membrane repair. Resealing of disrupted plasma membranes required external Ca2+ that could be antagonised by Mg2+. Block of Ca2+/calmodulin kinase II, which regulates exocytotic vesicle availability at synapses (Llinás et al., 1991), inhibited membrane resealing. Resealing was also inhibited by botulinum neurotoxins A, B, C1, and tetanus toxin, which disrupt SNARE vesicle docking/fusion proteins. Confocal microscopic observations of exocytotic events in sea urchin eggs and embryos during membrane resealing showed that inhibition of kinesin or myosin motor activity, which are believed to be required for vesicle transport (Goodson et al., 1997), also inhibited membrane resealing and delivery of vesicles to sites of membrane disruption. This pattern of inhibition indicates that membrane repair of micrometre-sized lesions requires vesicle delivery, docking and fusion, similar to the exocytosis of neurotransmitter (Steinhardt et al., 1994; Bi et al., 1995, 1997).The mechanism of resealing in eggs and embyros was found to be a general property of all cells (Steinhardt et al., 1994; Togo et al., 1999). It is now known that elevated intracellular Ca2+ triggers exocytosis in various types of cells (Dan & Poo, 1992; Coorssen et al., 1996), and that endosomal compartments such as lysosomes can behave as Ca2+-regulated exocytotic vesicles (Rodríguez et al., 1997).

scholarly journals Short-term transcriptomic response to plasma membrane injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Swantje Christin Häger ◽  
Catarina Dias ◽  
Stine Lauritzen Sønder ◽  
André Vidas Olsen ◽  
Isabelle da Piedade ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Repair ◽  
Short Term ◽  
Post Injury ◽  
Membrane Injury ◽  
Transcriptomic Response ◽  
A Genome ◽  
Ionic Detergent ◽  
Membrane Resealing ◽  
Regeneration Phase

AbstractPlasma membrane repair mechanisms are activated within seconds post-injury to promote rapid membrane resealing in eukaryotic cells and prevent cell death. However, less is known about the regeneration phase that follows and how cells respond to injury in the short-term. Here, we provide a genome-wide study into the mRNA expression profile of MCF-7 breast cancer cells exposed to injury by digitonin, a mild non-ionic detergent that permeabilizes the plasma membrane. We focused on the early transcriptional signature and found a time-dependent increase in the number of differentially expressed (> twofold, P < 0.05) genes (34, 114 and 236 genes at 20-, 40- and 60-min post-injury, respectively). Pathway analysis highlighted a robust and gradual three-part transcriptional response: (1) prompt activation of immediate-early response genes, (2) activation of specific MAPK cascades and (3) induction of inflammatory and immune pathways. Therefore, plasma membrane injury triggers a rapid and strong stress and immunogenic response. Our meta-analysis suggests that this is a conserved transcriptome response to plasma membrane injury across different cell and injury types. Taken together, our study shows that injury has profound effects on the transcriptome of wounded cells in the regeneration phase (subsequent to membrane resealing), which is likely to influence cellular status and has been previously overlooked.

scholarly journals An actin-dependent annexin complex mediates plasma membrane repair in muscle

2016 ◽  
Vol 213 (6) ◽  
pp. 705-718 ◽  
Author(s):  
Alexis R. Demonbreun ◽  
Mattia Quattrocelli ◽  
David Y. Barefield ◽  
Madison V. Allen ◽  
Kaitlin E. Swanson ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Muscle Fibers ◽  
Membrane Repair ◽  
Muscle Plasma Membrane ◽  
Shoulder Region ◽  
Plasma Membrane Repair ◽  
Molecular Machinery ◽  
Membrane Resealing ◽  
Efficient Recovery ◽  
High Resolution Microscopy

Disruption of the plasma membrane often accompanies cellular injury, and in muscle, plasma membrane resealing is essential for efficient recovery from injury. Muscle contraction, especially of lengthened muscle, disrupts the sarcolemma. To define the molecular machinery that directs repair, we applied laser wounding to live mammalian myofibers and assessed translocation of fluorescently tagged proteins using high-resolution microscopy. Within seconds of membrane disruption, annexins A1, A2, A5, and A6 formed a tight repair “cap.” Actin was recruited to the site of damage, and annexin A6 cap formation was both actin dependent and Ca2+ regulated. Repair proteins, including dysferlin, EHD1, EHD2, MG53, and BIN1, localized adjacent to the repair cap in a “shoulder” region enriched with phosphatidlyserine. Dye influx into muscle fibers lacking both dysferlin and the related protein myoferlin was substantially greater than control or individual null muscle fibers, underscoring the importance of shoulder-localized proteins. These data define the cap and shoulder as subdomains within the repair complex accumulating distinct and nonoverlapping components.

scholarly journals Exploitation of Marine-Derived Robust Biological Molecules to Manage Inflammatory Bowel Disease

Marine Drugs ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 196
Author(s):  
Muhammad Bilal ◽  
Leonardo Vieira Nunes ◽  
Marco Thúlio Saviatto Duarte ◽  
Luiz Fernando Romanholo Ferreira ◽  
Renato Nery Soriano ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bioactive Compounds ◽  
Bowel Disease ◽  
Clinical Translation ◽  
Biologically Active ◽  
Naturally Occurring ◽  
Inflammatory Bowel ◽  
Functional Features ◽  
Biological Entities ◽  
The Impact

Naturally occurring biological entities with extractable and tunable structural and functional characteristics, along with therapeutic attributes, are of supreme interest for strengthening the twenty-first-century biomedical settings. Irrespective of ongoing technological and clinical advancement, traditional medicinal practices to address and manage inflammatory bowel disease (IBD) are inefficient and the effect of the administered therapeutic cues is limited. The reasonable immune response or invasion should also be circumvented for successful clinical translation of engineered cues as highly efficient and robust bioactive entities. In this context, research is underway worldwide, and researchers have redirected or regained their interests in valorizing the naturally occurring biological entities/resources, for example, algal biome so-called “treasure of untouched or underexploited sources”. Algal biome from the marine environment is an immense source of excellence that has also been demonstrated as a source of bioactive compounds with unique chemical, structural, and functional features. Moreover, the molecular modeling and synthesis of new drugs based on marine-derived therapeutic and biological cues can show greater efficacy and specificity for the therapeutics. Herein, an effort has been made to cover the existing literature gap on the exploitation of naturally occurring biological entities/resources to address and efficiently manage IBD. Following a brief background study, a focus was given to design characteristics, performance evaluation of engineered cues, and point-of-care IBD therapeutics of diverse bioactive compounds from the algal biome. Noteworthy potentialities of marine-derived biologically active compounds have also been spotlighted to underlying the impact role of bio-active elements with the related pathways. The current review is also focused on the applied standpoint and clinical translation of marine-derived bioactive compounds. Furthermore, a detailed overview of clinical applications and future perspectives are also given in this review.

scholarly journals Plasma membrane integrity in health and disease: significance and therapeutic potential

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Catarina Dias ◽  
Jesper Nylandsted
Keyword(s):  
Plasma Membrane ◽  
Therapeutic Potential ◽  
Calcium Influx ◽  
Membrane Integrity ◽  
Cell Types ◽  
Physical Parameters ◽  
Membrane Repair ◽  
Plasma Membrane Integrity ◽  
Repair Mechanisms ◽  
And Function

AbstractMaintenance of plasma membrane integrity is essential for normal cell viability and function. Thus, robust membrane repair mechanisms have evolved to counteract the eminent threat of a torn plasma membrane. Different repair mechanisms and the bio-physical parameters required for efficient repair are now emerging from different research groups. However, less is known about when these mechanisms come into play. This review focuses on the existence of membrane disruptions and repair mechanisms in both physiological and pathological conditions, and across multiple cell types, albeit to different degrees. Fundamentally, irrespective of the source of membrane disruption, aberrant calcium influx is the common stimulus that activates the membrane repair response. Inadequate repair responses can tip the balance between physiology and pathology, highlighting the significance of plasma membrane integrity. For example, an over-activated repair response can promote cancer invasion, while the inability to efficiently repair membrane can drive neurodegeneration and muscular dystrophies. The interdisciplinary view explored here emphasises the widespread potential of targeting plasma membrane repair mechanisms for therapeutic purposes.

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