Structural and signaling role of lipids in plasma membrane repair

Deficits in plasma membrane repair have been identified in dysferlinopathy and Duchenne Muscular Dystrophy, and contribute to progressive myopathy. Although Facioscapulohumeral Muscular Dystrophy (FSHD) shares clinicopathological features with these muscular dystrophies, it is unknown if FSHD is characterized by plasma membrane repair deficits. Therefore, we exposed immortalized human FSHD myoblasts, immortalized myoblasts from unaffected siblings, and myofibers from a murine model of FSHD (FLExDUX4) to focal, pulsed laser ablation of the sarcolemma. Repair kinetics and success were determined from the accumulation of intracellular FM1-43 dye post-injury. We subsequently treated FSHD myoblasts with a DUX4-targeting antisense oligonucleotide (AON) to reduce DUX4 expression, and with the antioxidant Trolox to determine the role of DUX4 expression and oxidative stress in membrane repair. Compared to unaffected myoblasts, FSHD myoblasts demonstrate poor repair and a greater percentage of cells that failed to repair, which was mitigated by AON and Trolox treatments. Similar repair deficits were identified in FLExDUX4 myofibers. This is the first study to identify plasma membrane repair deficits in myoblasts from individuals with FSHD, and in myofibers from a murine model of FSHD. Our results suggest that DUX4 expression and oxidative stress may be important targets for future membrane-repair therapies.

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ANO5 ensures trafficking of annexins in wounded myofibers

The Journal of Cell Biology ◽

10.1083/jcb.202007059 ◽

2021 ◽

Vol 220 (3) ◽

Author(s):

Steven J. Foltz ◽

Yuan Yuan Cui ◽

Hyojung J. Choo ◽

H. Criss Hartzell

Keyword(s):

Plasma Membrane ◽

Fine Structure ◽

Muscular Dystrophy ◽

Knockout Mice ◽

Annexin A2 ◽

Limb Girdle Muscular Dystrophy ◽

Membrane Repair ◽

Phospholipid Scramblase ◽

Plasma Membrane Repair

Mutations in ANO5 (TMEM16E) cause limb-girdle muscular dystrophy R12. Defective plasma membrane repair is a likely mechanism. Using myofibers from Ano5 knockout mice, we show that trafficking of several annexin proteins, which together form a cap at the site of injury, is altered upon loss of ANO5. Annexin A2 accumulates at the wound to nearly twice the level observed in WT fibers, while annexin A6 accumulation is substantially inhibited in the absence of ANO5. Appearance of annexins A1 and A5 at the cap is likewise diminished in the Ano5 knockout. These changes are correlated with an alteration in annexin repair cap fine structure and shedding of annexin-positive vesicles. We conclude that loss of annexin coordination during repair is disrupted in Ano5 knockout mice and underlies the defective repair phenotype. Although ANO5 is a phospholipid scramblase, abnormal repair is rescued by overexpression of a scramblase-defective ANO5 mutant, suggesting a novel, scramblase-independent role of ANO5 in repair.

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Faculty Opinions recommendation of Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1028188.341132 ◽

2005 ◽

Author(s):

Brigitte Huber

Keyword(s):

Plasma Membrane ◽

Membrane Repair ◽

Plasma Membrane Repair ◽

Induction Of Apoptosis ◽

Ctl Induction

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Plasma membrane repairs by small GTPase Rab3a

The Journal of Cell Biology ◽

10.1083/jcb.201606006 ◽

2016 ◽

Vol 213 (6) ◽

pp. 613-615 ◽

Cited By ~ 2

Author(s):

Camilla Raiborg ◽

Harald Stenmark

Keyword(s):

Plasma Membrane ◽

Small Gtpase ◽

Membrane Repair ◽

Cell Biol ◽

Plasma Membrane Repair

Lysosomes fuse with the plasma membrane to help repair membrane lesions, but how they are positioned close to these lesions is not fully understood. Now, Encarnação et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201511093) demonstrate that the lysosomal GTPase Rab3a and its effectors orchestrate lysosome positioning and plasma membrane repair.

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Mitochondrial fragmentation enables localized signaling required for cell repair

The Journal of Cell Biology ◽

10.1083/jcb.201909154 ◽

2020 ◽

Vol 219 (5) ◽

Cited By ~ 3

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.

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