A conserved annexin A6–mediated membrane repair mechanism in muscle, heart, and nerve

Demonbreun, Alexis R.; Bogdanovic, Elena; Vaught, Lauren A.; Reiser, Nina L.; Fallon, Katherine S.; Long, Ashlee M; Oosterbaan, Claire C.; Hadhazy, Michele; Page, Patrick; Joseph, Prem Raj B.; Cowen, Gabrielle; Telenson, Alexander M.; Khatri, Ammaarah; Sadleir, Katherine R.; Vassar, Robert; McNally, Elizabeth M.

doi:10.1172/jci.insight.158107

Cited by 15 publications

(22 citation statements)

References 76 publications

(89 reference statements)

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“…After recruitment, both ANXA4 and ANXA6 act in concert, therefore, the capacity of ANXA4 and ANXA6 to mix on a membrane surface is an important piece of supporting data for the Boye et al model 6 . It should be noted here however, that our discussion of ANXA6 only refers to its role in PMR as it binds to membranes and therefore our findings to not contradict the self-interaction described in the ANXA6 repair cap model 21,22 .…”

Section: Localization Of Crosslinkers During Membrane Patch Rollingsupporting

confidence: 42%

Interplay of membrane crosslinking and curvature induction by annexins

Mularski

Sønder

Heitmann

et al. 2022

Sci Rep

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Efficient plasma membrane repair (PMR) is required to repair damage sustained in the cellular life cycle. The annexin family of proteins, involved in PMR, are activated by Ca2+ influx from extracellular media at the site of injury. Mechanistic studies of the annexins have been overwhelmingly performed using a single annexin, despite the recruitment of multiple annexins to membrane damage sites in living cells. Hence, we investigate the effect of the presence of the crosslinking annexins, annexin A1, A2 and A6 (ANXA1, ANXA2 and ANXA6) on the membrane curvature induction of annexin A4 (ANXA4) in model membrane systems. Our data support a mechanistic model of PMR where ANXA4 induced membrane curvature and ANXA6 crosslinking promotes wound closure. The model now can be expanded to include ANXA1 and ANXA2 as specialist free edge membrane crosslinkers that act in concert with ANXA4 induced curvature and ANXA6 crosslinking.

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Section: Localization Of Crosslinkers During Membrane Patch Rollingsupporting

confidence: 42%

Interplay of membrane crosslinking and curvature induction by annexins

Mularski

Sønder

Heitmann

et al. 2022

Sci Rep

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“…[23] Yet another pool of not precisely defined intracellular vesicles has been implicated to support membrane wound closure by lowering the membrane tension which is increased upon damage. [4,19,24] Thus, so far no consensus has been reached on the still ambiguous sources of membrane required for resealing, and recent studies have rather focused on the context-dependent molecular players [25][26][27] or the later stages of repair after a diffusion barrier has been reestablished. [28,29] The ambiguity concerning the source of membrane for the repair process has been also augmented by the lack of studies on the spatio-temporal membrane dynamics that occur immediately after wounding in somatic cells, that is, within the first 20-30 s that comprise the time interval for resealing.…”

Section: Introductionmentioning

confidence: 99%

Early Endosomes Act as Local Exocytosis Hubs to Repair Endothelial Membrane Damage

et al. 2023

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The plasma membrane of a cell is subject to stresses causing ruptures that must be repaired immediately to preserve membrane integrity and ensure cell survival. Yet, the spatio‐temporal membrane dynamics at the wound site and the source of the membrane required for wound repair are poorly understood. Here, it is shown that early endosomes, previously only known to function in the uptake of extracellular material and its endocytic transport, are involved in plasma membrane repair in human endothelial cells. Using live‐cell imaging and correlative light and electron microscopy, it is demonstrated that membrane injury triggers a previously unknown exocytosis of early endosomes that is induced by Ca2+ entering through the wound. This exocytosis is restricted to the vicinity of the wound site and mediated by the endosomal soluble N‐ethylmaleimide sensitive factor attachment protein receptor (SNARE) VAMP2, which is crucial for efficient membrane repair. Thus, the newly identified Ca2+‐evoked and localized exocytosis of early endosomes supplies the membrane material required for rapid resealing of a damaged plasma membrane, thereby providing the first line of defense against damage in mechanically challenged endothelial cells.

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“…Calcium-binding proteins, molecular chaperones, cell adhesion molecules, cytoskeletal, scaffold and membrane trafficking proteins were found among the most enriched categories in the EVs released by intoxicated cells ( Figure 5 D and Table 1 ). In particular, we detected several annexins ( Table 1 ), which have been extensively described as key players in Ca 2+ -driven repair responses [ 21 , 26 , 37 , 38 , 39 ]. Chaperones and cytoskeletal proteins were also previously reported to be essential for effective repair of damage caused by CDCs [ 13 , 16 ].…”

Section: Resultsmentioning

confidence: 99%

Cells Responding to Closely Related Cholesterol-Dependent Cytolysins Release Extracellular Vesicles with a Common Proteomic Content Including Membrane Repair Proteins

Alves

Pereira

Mayer

et al. 2022

Toxins

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The plasma membrane (PM) protects cells from extracellular threats and supports cellular homeostasis. Some pathogens produce pore-forming toxins (PFTs) that disrupt PM integrity by forming transmembrane pores. High PFT concentrations cause massive damage leading to cell death and facilitating infection. Sub-lytic PFT doses activate repair mechanisms to restore PM integrity, support cell survival and limit disease. Shedding of extracellular vesicles (EVs) has been proposed as a key mechanism to eliminate PFT pores and restore PM integrity. We show here that cholesterol-dependent cytolysins (CDCs), a specific family of PFTs, are at least partially eliminated through EVs release, and we hypothesize that proteins important for PM repair might be included in EVs shed by cells during repair. To identify new PM repair proteins, we collected EVs released by cells challenged with sub-lytic doses of two different bacterial CDCs, listeriolysin O and pneumolysin, and determined the EV proteomic repertoire by LC-MS/MS. Intoxicated cells release similar EVs irrespectively of the CDC used. Also, they release more and larger EVs than non-intoxicated cells. A cluster of 70 proteins including calcium-binding proteins, molecular chaperones, cytoskeletal, scaffold and membrane trafficking proteins, was detected enriched in EVs collected from intoxicated cells. While some of these proteins have well-characterized roles in repair, the involvement of others requires further study. As proof of concept, we show here that Copine-1 and Copine-3, proteins abundantly detected in EVs released by intoxicated cells, are required for efficient repair of CDC-induced PM damage. Additionally, we reveal here new proteins potentially involved in PM repair and give new insights into common mechanisms and machinery engaged by cells in response to PM damage.

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A conserved annexin A6–mediated membrane repair mechanism in muscle, heart, and nerve

Cited by 15 publications

References 76 publications

Interplay of membrane crosslinking and curvature induction by annexins

Interplay of membrane crosslinking and curvature induction by annexins

Early Endosomes Act as Local Exocytosis Hubs to Repair Endothelial Membrane Damage

Cells Responding to Closely Related Cholesterol-Dependent Cytolysins Release Extracellular Vesicles with a Common Proteomic Content Including Membrane Repair Proteins

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