Annexin A7 is required for ESCRT III-mediated plasma membrane repair

Sønder, Stine Lauritzen; Boye, Theresa Louise; Tölle, Regine C; Dengjel, Jörn; Maeda, Kenji; Jäättelä, Marja; Simonsen, Adam Cohen; Jaiswal, Jyoti K.; Nylandsted, Jesper

doi:10.1038/s41598-019-43143-4

Cited by 80 publications

(102 citation statements)

References 44 publications

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“…A possible drawback is that membrane damage triggered by UV-ablation laser induces local high temperatures at the injured membrane, which can potentially affect membrane proteins and lipids and create thermally-induced diffusion and denaturation artifacts. However, we and others have demonstrated tempo-spatial recruitment of repair proteins occurs within 10-45s of laser-induced plasma membrane injury [28,44], indicating that the repair machinery is not disabled by the collateral thermal damage. Importantly, complimentary methods to induce membrane injury, such as the use of glass bead injury, detergents, and scraping, show that the same repair proteins are recruited to damaged membrane (including annexins, actin, ESCRT III) as with laser injury and needed for repair [14,45].…”

Section: Approaches To Inflict Damage To the Plasma Membranementioning

confidence: 60%

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

Bendix

Simonsen

Florentsen

et al. 2020

Cells

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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 Ca 2+ -and phospholipid-binding annexin proteins. Upon membrane damage, annexin family members are activated by a Ca 2+ 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.

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Section: Approaches To Inflict Damage To the Plasma Membranementioning

confidence: 60%

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

Bendix

Simonsen

Florentsen

et al. 2020

Cells

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“…We therefore wanted to investigate if Mtb could damage the macrophage PM, and if this could be involved in inflammasome activation by Mtb. To monitor PM integrity, we made a THP-1 reporter cell line with an mNeonGreen fluorescent protein tag on the Ca2+ binding protein Apoptosis-Linked Gene 2 (ALG-2), which is recruited to sites of PM damage by calcium influx 69–71 . We imaged Mtb-BFP infected THP-1 macrophages by time-lapse confocal microscopy and observed ALG-2 recruitment in infected cells, almost 90% of which occurred in close vicinity to Mtb bacteria (Figure 6a, b and Movies S14 and S15).…”

Section: Resultsmentioning

confidence: 99%

“…Strikingly, the opposite case with extensive, but localized and controlled lysosomal damage caused by a lysosomal photosensitiser does not cause NLRP3 activation. Since PM damage is actively repaired through many routes, including through Ca2+ - dependent ESCRT machinery 44, 69–71 , it is also interesting to note that this branch of ESCRT emerges as a negative regulator of NLRP3 activation and cell death during Mtb infection. The ESCRT machinery was also recently shown to be involved in repair of phagosomes damaged by mycobacteria 84, 85 and to regulate pyroptosis or necroptosis by repairing GSDMD pores 86 or MLKL pores 87 , respectively, further pointing to the importance of the ESCRT machinery in regulation of inflammation and securing cell viability.…”

Section: Discussionmentioning

confidence: 99%

Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection

Beckwith

Ullmann

et al. 2019

Preprint

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AbstractMycobacterium tuberculosis (Mtb) is a major global health problem and causes extensive cytotoxicity in patient cells and tissues. Here we define an NLRP3, caspase-1 and gasdermin D-mediated pathway to pyroptosis in human monocytes following exposure to Mtb. We demonstrate an ESX-1 mediated, contact-induced plasma membrane (PM) damage response that occurs during phagocytosis or from the cytosolic side of the PM after phagosomal rupture in Mtb infected cells. This PM injury in turn causes K+ efflux and activation of NLRP3 dependent IL-1β release and pyroptosis, facilitating the spread of Mtb to neighbouring cells. Further we reveal a dynamic interplay of pyroptosis with ESCRT-mediated PM repair. Collectively, these findings reveal a novel mechanism for pyroptosis and spread of infection acting through dual PM disturbances both during and after phagocytosis. We also highlight dual PM damage as a common mechanism utilized by other NLRP3 activators that have previously been shown to act through lysosomal damage.Graphical abstract

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“…We conclude that the repair defect in ANO5-deficient muscle is independent of dysferlin. 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.…”

Section: Introductionmentioning

confidence: 99%

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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Annexin A7 is required for ESCRT III-mediated plasma membrane repair

Cited by 80 publications

References 44 publications

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

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

Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection

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

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