Recombinant annexin A6 promotes membrane repair and protects against muscle injury

Demonbreun, Alexis R.; Fallon, Katherine S.; Oosterbaan, Claire C.; Bogdanovic, Elena; Warner, James L.; Sell, Jordan; Page, Patrick; Quattrocelli, Mattia; Barefield, David; McNally, Elizabeth M.

doi:10.1172/jci128840

Cited by 57 publications

(79 citation statements)

References 61 publications

(87 reference statements)

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“…ANXA2 has been shown to foster membrane blebbing, presumably through binding to the outer surface of membrane lesions, while both ANXA2 and ANXA6 are capable of inducing "membrane folding," which involves binding and pulling together membranes. ANXA6 in particular has been suggested as a key factor in collapsing membrane lesions because it has two annexin cores and can consequently bind two membranes (41,76). We identified depressed trafficking of ANXA6 overall in ANO5-KO myofibers, which is consistent with delayed plasma membrane resealing.…”

Section: Discussionsupporting

confidence: 69%

“…Annexins are phospholipid binding proteins with established roles in plasma membrane repair in various cell types (53,(56)(57)(58)(59). Specifically in muscle, ANXA1, ANXA2, ANXA5, ANXA6 (mouse (38)(39)(40)(41)44)) and ANXA11 (zebrafish (42)) have been implicated in sarcolemmal resealing after injury. Annexins form a punctate "cap" that first appears within seconds of wounding, but continues to grow on a timescale of minutes (40,42).…”

Section: Introductionmentioning

confidence: 99%

“…1A, B). It should be noted that ANO5 may play a role in Ca 2+ homeostasis (8) and that this may contribute to the observed changes in the post-injury Ca 2+ transients in ANO5-KO myofibers.Second, we employed a common damage assay based on the cell-impermeant dye [39][40][41]45,52). FM1-43 is a water-soluble stearyl dye that is not fluorescent in aqueous solution, but fluoresces intensely when inserted into lipid-rich membranes.…”

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confidence: 99%

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Defective Trafficking of Annexins to the Site of Injury in ANO5-Knockout Muscle Fibers

Foltz

Cui

Choo

et al. 2020

Preprint

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Mutations in ANO5 (TMEM16E) cause limb-girdle muscular dystrophy R12 (limb-girdle muscular dystrophy type 2L). Recent evidence implicates defective plasma membrane repair as a likely mechanism for the disorder. Here, we probe the ANO5-dependency of the membrane repair pathway using a laser wounding assay in Ano5 knockout mouse muscle fibers. Wounded myofibers from Ano5 knockout mice exhibit delayed membrane resealing relative to wild type fibers as revealed by an increased uptake of the membrane-impermeant FM1-43 dye and a prolonged elevation of intracellular Ca 2+ . The trafficking of several annexin proteins, which together form a cap at the site of injury, is altered in Ano5 knockout fibers. 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. Furthermore, trafficking of annexins A1 and A5 to the cap is decreased in the Ano5 knockout. These changes are correlated with an alteration in the fine structure of the annexin repair cap and the shedding of annexin-positive extracellular vesicles. Our results suggest that the meticulous coordination of the annexin repair machinery required to effectively reseal wounded sarcolemma is disrupted in Ano5 knockout mice. ANO5 is a putative phospholipid scramblase, responsible for exposure of intracellular phospholipids to the extracellular leaflet of the plasma membrane. However, because the membrane repair defect is rescued by overexpression of wild type ANO5 or a scramblase-defective mutant, we suggest that ANO5-mediated phospholipid scrambling is not essential for membrane repair. Significance StatementMutations in ANO5/TMEM16E cause myopathies of variable severity, with some patients losing ambulation entirely. Unfortunately, relatively little is known about the function of ANO5 at the protein level, but it has been suggested that ANO5 plays a role in the repair of injured muscle plasma membranes. Here, we investigate the mechanism of ANO5-mediated repair and find that annexin proteins, which in normal muscle form a cap to seal wounds, traffic abnormally to the cap when ANO5 is not expressed. Muscle fibers lacking ANO5 reseal more slowly and thus are exposed to prolonged intracellular calcium elevation that can damage the fibers. Our findings contribute to the growing literature implicating failed repair as a probable pathogenic mechanism in patients with ANO5 mutations.Recessive mutations in the ANO5 gene are responsible for a spectrum of myopathies with variable severity. These disorders, which are characterized by muscle weakness and atrophy, include limb girdle muscular dystrophy R12 (LGMDR12/LGMD2L), Miyoshi muscular dystrophy type 3 (MMD3), and muscle weakness with myalgia and rhabdomyolysis (1-4). Since ANO5-myopathies were discovered in 2010 (1), >70 ANO5 variants have been reported to be pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/). In a recent screen of 35 LGMD genes in 4656 clinically-suspected LGMD patients, ANO5 was the 4 th most likely cont...

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Defective Trafficking of Annexins to the Site of Injury in ANO5-Knockout Muscle Fibers

Foltz

Cui

Choo

et al. 2020

Preprint

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“…[31][32][33] These modifiers may affect the onset age of the disease, the affected muscle groups, and the severity and prognosis of the disease in muscular dystrophies. [31][32][33][34][35][36][37][38][39][40][41][42] These modifiers may also explain the cognitive impairment seen in NC-Ms.…”

Section: Discussionmentioning

confidence: 99%

Cognition of the mothers of patients with Duchenne muscular dystrophy

et al. 2020

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Duchenne muscular dystrophy (DMD) has been found to be associated with cognitive impairment. However, few studies have addressed cognitive impairment among mothers of children with DMD. In the present study, the neuropsychological profiles of both carrier mothers (C-Ms) and noncarrier mothers (NC-Ms) were examined, and the findings were compared with healthy control mothers (HC-Ms). There were 90 participants, consisting of 31 C-Ms, 24 NC-Ms, and 35 HC-Ms, each of whom completed a neuropsychological test battery. C-Ms had poorer cognition performance in attention, working memory, immediate verbal memory, visuospatial skills, and executive functions than NC-Ms, and HC-Ms. This study provides evidence that there may be cognitive impairment in mothers of patients with DMD. The cognitive impairment of C-Ms has similarities to that seen in children with DMD.

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“…We confirmed that binding to surface-associated antigen induces B-cell PM permeabilization by using membrane-impermeable, fluorescent lipophilic FM probes. These dyes are used extensively for detecting PM permeabilization, because they only label the outer PM leaflet in intact cells but rapidly stain intracellular membranes when entering cells (Bansal et al 2003;McNeil et al 2003;Demonbreun et al 2019). After >30 min of interaction with αM-PLB we observed sudden, massive increases in intracellular FM associated with intracellular structures, including the nuclear envelope ( Figure 1K Sudden FM influx was only observed in B-cells that eventually became PI-positive, but not in cells that remained PI-negative during interaction with αM-PLB.…”

Section: Bcr Interaction With Surface-associated Antigen Induces B-cementioning

confidence: 99%

Surface-associated antigen induces B-cell permeabilization and lysosome exocytosis facilitating antigen uptake and presentation to T-cells

Maeda

Haaren

Langley

et al. 2020

Preprint

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B-cell receptor (BCR)-mediated antigen internalization and presentation are essential for humoral memory immune responses. Antigen encountered by B-cells is often tightly associated with the surface of pathogens and/or antigen-presenting cells. Internalization of such antigens requires myosin-mediated traction forces and extracellular release of lysosomal enzymes, but the mechanism triggering lysosomal exocytosis is unknown. Here we show that BCR-mediated high-affinity recognition of antigen tethered to beads or planar lipid-bilayers causes localized plasma membrane (PM) permeabilization, a process that requires BCR signaling and non-muscle myosin II activity. B-cell permeabilization triggers a PM repair response involving lysosomal exocytosis. B-cells transiently permeabilized by surface-associated antigen internalize more antigen than cells that remain intact, and higher affinity antigens that cause more B-cell permeabilization and lysosomal exocytosis are more efficiently presented to T-cells. Thus, PM permeabilization by surface-associated antigen triggers a lysosome-mediated B-cell resealing response, which provides the extracellular hydrolases that can facilitate antigen internalization and presentation.

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Recombinant annexin A6 promotes membrane repair and protects against muscle injury

Cited by 57 publications

References 61 publications

Defective Trafficking of Annexins to the Site of Injury in ANO5-Knockout Muscle Fibers

Defective Trafficking of Annexins to the Site of Injury in ANO5-Knockout Muscle Fibers

Cognition of the mothers of patients with Duchenne muscular dystrophy

Surface-associated antigen induces B-cell permeabilization and lysosome exocytosis facilitating antigen uptake and presentation to T-cells

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