Häger, Swantje Christin

Nylandsted, Jesper

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u n i ve r s i t y  o f  co pe n h ag e n  Københavns UniversitetAnnexinsHäger, Swantje Christin; Nylandsted, JesperPublished in:Communicative and Integrative BiologyDOI:10.1080/19420889.2019.1676139Publication date:2019Document versionPublisher's PDF, also known as Version of recordDocument license:CC BYCitation for published version (APA):Häger, S. C., & Nylandsted, J. (2019). Annexins: players of single cell wound healing and regeneration.Communicative and Integrative Biology, 12(1), 162-165. https://doi.org/10.1080/19420889.2019.1676139Download date: 03. Feb. 2020Full Terms & Conditions of access and use can be found athttps://www.tandfonline.com/action/journalInformation?journalCode=kcib20Communicative & Integrative BiologyISSN: (Print) 1942-0889 (Online) Journal homepage: https://www.tandfonline.com/loi/kcib20Annexins: players of single cell wound healing andregenerationSwantje Christin Häger & Jesper NylandstedTo cite this article: Swantje Christin Häger & Jesper Nylandsted (2019) Annexins: players of singlecell wound healing and regeneration, Communicative & Integrative Biology, 12:1, 162-165, DOI:10.1080/19420889.2019.1676139To link to this article:  https://doi.org/10.1080/19420889.2019.1676139© 2019 The Author(s). Published by InformaUK Limited, trading as Taylor & FrancisGroup.Accepted author version posted online: 07Oct 2019.Published online: 13 Oct 2019.Submit your article to this journal Article views: 145View related articles View Crossmark dataSHORT COMMUNICATIONAnnexins: players of single cell wound healing and regenerationSwantje Christin Hägera and Jesper Nylandsteda,baMembrane Integrity, Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center,Copenhagen, Denmark; bDepartment of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen,Copenhagen, DenmarkABSTRACTCell life is defined by a thin 4 nm plasma membrane, which separates the interior of a cell from itsenvironment. Thus, disruption of the plasma membrane poses a critical risk to cells, whichrequires immediate repair to avoid uncontrolled osmotic lysis and cell death. The initial repairresponse to stop the leakage usually occurs within 10–45 s and implicates Ca2+-activated phos-pholipid-binding proteins including annexins. We previously reported that annexin-induced cur-vature of lateral membrane around the hole plays an important role for immediate resealing ofhuman cancer cells. Once the breach has been sealed, the cell often regenerates itself byremoving the damaged membrane. This process, which also involves annexins includes excisionand shedding of damaged membrane implicating the endosomal sorting complex required fortransport (ESCRT) III and actin cytoskeleton remodeling. Hence, studies of cell membrane repairmechanisms should differentiate between the immediate repair response happening withinseconds and the subsequent regeneration phase, which occurs in the order of minutes to hoursafter injury.ARTICLE HISTORYReceived 6 September 2019Accepted 11 September 2019KEYWORDSPlasma membrane repair;annexins; initial repair;regeneration; cellmembrane; wound healingThe plasma membrane of eukaryotic cells constitutesthe “margin between life and death for individualcells”[1]. Moreover, the plasma membrane in combina-tion with the cytoskeleton defines the cell shape, facil-itates cell-cell contacts and can anchor cells to thesurrounding extracellular matrix. It is therefore crucialthat the plasma membrane is kept intact, both for cellsurvival and for the cell system as a whole to remainwell-functioning [2]. Once the cell has healed, it facesthe issue of regenerating damaged cellular structuresincluding the area around the injured membrane.Focused research within plasma membrane repairmechanisms started in the 1990s, which seems late givingthe fundamental importance of this mechanism for cellviability [3]. However, the field is gaining increasingattention. This is mainly driven by the association ofmembrane repair with several diseases where the stron-gest link between repair deficiency and disease pathologyis observed for muscular dystrophies that lead to gradualmuscle wasting and weakening [4,5]. On the other hand,our findings reveal that cancer cells are a counterexampleto repair-deficient diseases, since they appear to be moredependent on efficient plasma membrane repair to copewith the physical stress imposed on them due to theirinvasive behavior [6,7]. Importantly, novel biophysicaltechniques to better address plasma membrane repairmechanisms have been introduced lately and further pro-moted research in this field.Membrane integrity is governed by several repairand regeneration mechanisms that are likely to be uti-lized in combination depending on the kind of injuryimposed on the membrane. One important hallmark inthe repair response is influx of Ca2+ through the mem-brane lesion due to a more than a thousandfold con-centration gradient between the extracellular space andthe cytoplasm [8]. Ca2+ influx triggers the rapid recruit-ment of repair proteins within 10–45 s to the injuredmembrane [9]. This initial recruitment of Ca2+-activated repair proteins such as annexins correlateswith the time frame needed to seal a membrane holeto avoid excessive leakage of cell mass [10,11]. Thus,the damage response can be considered as a two-phaseprocess: First, an immediate repair response to quicklyseal the hole, and secondly – a regeneration phase tofully reestablish the membrane upon damage [12](Figure 1). Although mechanisms of single-cell regen-eration upon injury are poorly characterized these pro-cesses appear to depend on strategies to removedamaged membrane by endocytic mechanisms and byshedding of injured membrane.CONTACT Jesper Nylandsted jnl@cancer.dk Membrane Integrity, Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, DanishCancer Society Research Center, Strandboulevarden 49, Copenhagen 2100, DenmarkCOMMUNICATIVE & INTEGRATIVE BIOLOGY2019, VOL. 12, NO. 1, 162–165https://doi.org/10.1080/19420889.2019.1676139© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricteduse, distribution, and reproduction in any medium, provided the original work is properly cited.The cellular damage response can trigger the fusionof intracellular compartments with each other and theplasma membrane, which led to the patch hypothesis; itsuggests that intracellular organelles fuse to form animpermeant patch at the damaged membrane [13].While patching has been observed in large cell typessuch as eggs and oocytes of echinoderms [14] andamphibians [15] the process appears to be too slowalone to account for the rapid initial resealing (within10–45 s) observed in many mammalian cell types.Moreover, we have not detected any patch formationduring repair of human cancer cells such as HeLacervix carcinoma and MCF7 breast carcinoma cells[6]. Our results support an alternative model in mam-malian cells where lateral recruitment of membranearound the hole is used for resealing as reported froma mouse model of dysferlin-deficient muscular dystro-phy [16]. Here, the membrane necessary for resealing isderived from the surrounding sarcolemma, enrichedand then fused at the wound site [16]. In line withthis, we have seen related repair responses implicatingthe manipulation of wound edges and lateral mem-brane in breast cancer cells upon wounding by ablationlaser [17]. This response involves several annexinfamily members that upon injury to the plasmamembrane and Ca2+ influx are rapidly recruited tothe damaged membrane. To this end, we have assessedthe impact of nine annexin family members (ANXA1-ANXA7, ANXA11, ANXA13) on supported membranepatches with free edges – a model system relevant formimicking the condition around a membrane hole[18]. Interestingly, we found that a common character-istic of annexins is their ability to generate membranecurvature on anionic membranes, which seems to beimportant for their function during repair [18].Upon plasma membrane injury, ANXA4 and ANXA6are recruited to the damaged membrane and bind to andin the vicinity of wound edges. Here, self-association ofANXA4 into trimers induces out-of-plane curvature ofmembrane edges, whereas ANXA6 appears to trigger in-plane constriction of hole edges. The combination ofthese forces acts to pull the membrane edges togethertoward wound closure [17,19]. Moreover, we find thatseveral other annexin family members bind around theinjury site and may contribute by bending lateral mem-brane and glue adjacent membranes together [20]. Thus,the initial resealing response is likely orchestrated byannexin family members that are recruited to the injuredmembrane within the appropriate time frame (10–45 s)for rapid resealing. Once the initial leakage is stopped, theFigure 1. Model for plasma membrane repair in mammalian cells that discriminates between initial resealing and subsequent regenera-tion. Injury to the membrane and influx of Ca2+ ions into the cytoplasm activate annexin proteins that are recruited to the damagedmembrane within 10-45 s. Here, ANXA4 and ANXA6 induce out-of-plane curvature and in-plane constriction, respectively, which incollaboration with other annexin family members enriches lateral membrane and promotes wound closure. Upon initial resealing, cellsstart to regenerate their membrane by shedding damaged membrane and/or by internalization (not shown). Excision of larger membraneareas requires F-actin buildup, which is regulated by ANXA2 protein at the injured membrane. Smaller membrane pieces are shedded inthe form of ectosomes – a process that is facilitated by the ESCRT III complex. ANXA7 is needed to position and attach the ESCRT IIIcomponents ALG-2 and ALG-2-interacting protein X (ALIX) at the injured membrane during this phase.COMMUNICATIVE & INTEGRATIVE BIOLOGY 163cell starts to regenerate and restructure the membraneoften by removing the initially damaged membrane viashedding of damaged membrane and/or endocytosis(Figure 1). Some annexins are involved in this phase aswell, and we have revealed that ANXA2 in a complex withS100A11 facilitates local cortical F-actin polymerization,which is required to excise the damaged part of theplasma membrane[6]. Since ANXA2 is recruited early, itprobably serves a dual role by first facilitating curvatureand fusion of lateral membrane at the wound site, andsecondly to direct actin polymerization to restructure andexcise the wounded part of the membrane.Our recent data show that another annexin, ANXA7,which was the first annexin family member to be dis-covered [21], is involved in regenerating the plasmamembrane upon damage [20]. Cells actively sheddamaged membrane by ectocytosis through the endo-somal sorting complex required for transport (ESCRT)III. The ESCRT III complex assembles spirally aroundthe damaged membrane followed by contraction, whichleads to shedding of membrane in the form of ecto-somes. Here, the Ca2+-binding protein apoptosis-linkedgene-2 (ALG-2) is needed to assemble the ESCRT IIIcomplex [22,23]. While ALG-2 lacks membrane-binding capability we found that ANXA7 is used torecruit and attach ALG-2 and ALG-2-interacting pro-tein X (ALIX) to the damaged membrane. Thus,ANXA7 can initiate the process of ESCRT III buildupduring the regeneration process to shed damaged mem-brane [20].Single-cell membrane repair is an intriguing researchfield covering a wide panel of cellular processes, whichneed to be swiftly coordinated to reseal a torn membrane.However, how these processes are linked and regulated indetail is still unclear and requires further exploration.There seems to be some discrepancy between differentcell studies, which may simply reflect general cellularplasticity, i.e. that different cell types repair differently.Thus, more interdisciplinary research combining biophy-sics with cell biology should provide better mechanisticinsight into this fascinating repair response.Disclosure of potential conflicts of interestNo potential conflict of interest was reported by the authors.FundingThis work was partly funded by the Danish Council forIndependent Research, Natural Sciences [6108-00378A],Scientific Committee Danish Cancer Society [R90-A5847-14-S2](JN), and the Novo Nordisk Foundation [NNF18OC0034936].References[1] van Meer G, Voelker DR, Feigenson GW. Membranelipids: where they are and how they behave. Nat RevMol Cell Biol. 2008;9:112–124.[2] Lombard J. Once upon a time the cell membranes:175 years of cell boundary research. Biol Direct.2014;9:32.[3] McNeil PL, Ito S. Molecular traffic through plasmamembrane disruptions of cells in vivo. J Cell Sci.1990;96(Pt 3):549–556.[4] Bansal D, Campbell KP. Dysferlin and the plasmamembrane repair in muscular dystrophy. Trends CellBiol. 2004;14:206–213.[5] Lennon NJ, Kho A, Bacskai BJ, et al. Dysferlin interactswith annexins A1 and A2 and mediates sarcolemmalwound-healing. JBiolChem. 2003;278:50466–50473.[6] Jaiswal JK, Lauritzen SP, Scheffer L, et al. S100A11 isrequired for efficient plasma membrane repair andsurvival of invasive cancer cells. Nat Commun.2014;5:3795.[7] Jaiswal JK, Nylandsted J. S100 and annexin proteinsidentify cell membrane damage as the achilles heel ofmetastatic cancer cells. Cell Cycle. 2015;14:502–509.[8] Clapham DE. Calcium signaling. Cell.2007;131:1047–1058.[9] Draeger A, Monastyrskaya K, Babiychuk EB. Plasmamembrane repair and cellular damage control: theannexin survival kit. BiochemPharmacol.2011;81:703–712.[10] McNeil AK, Rescher U, Gerke V, et al. Requirement forannexin A1 in plasma membrane repair. JBiolChem.2006;281:35202–35207.[11] Bouter A, Gounou C, Berat R, et al. Annexin-A5assembled into two-dimensional arrays promotes cellmembrane repair. NatCommun. 2011;2:270.[12] Tang SKY, Marshall WF. Self-repairing cells: how sin-gle cells heal membrane ruptures and restore loststructures. Science. 2017;356:1022–1025.[13] McNeil PL, Vogel SS, Miyake K, et al. Patching plasmamembrane disruptions with cytoplasmic membrane.J Cell Sci. 2000;113(Pt 11):1891–1902.[14] Steinhardt RA, Bi G, Alderton JM. Cell membraneresealing by a vesicular mechanism similar to neuro-transmitter release. Science. 1994;263:390–393.[15] Clark AG, Miller AL, Vaughan E, et al. Integration ofsingle and multicellular wound responses. Curr Biol.2009;19:1389–1395.[16] McDade JR, Archambeau A, Michele DE. Rapidactin-cytoskeleton-dependent recruitment of plasmamembrane-derived dysferlin at wounds is critical formuscle membrane repair. Faseb J. 2014;28:3660–3670.[17] Boye TL, Maeda K, Pezeshkian W, et al. Annexin A4and A6 induce membrane curvature and constrictionduring cell membrane repair. Nat Commun.2017;8:1623.[18] Boye TL, Jeppesen JC, Maeda K, et al. Annexins inducecurvature on free-edge membranes displaying distinctmorphologies. Sci Rep. 2018;8:10309.[19] Simonsen AC, Boye TL, Nylandsted J. Annexins bendwound edges during plasma membrane repair. CurrMed Chem. 2019;26:1–11.164 S. C. HÄGER AND J. NYLANDSTED[20] Sonder SL, Boye TL, Tolle R, et al. Annexin A7 isrequired for ESCRT III-mediated plasma membranerepair. Sci Rep. 2019;9:6726.[21] Creutz CE, Pazoles CJ, Pollard HB. Identification andpurification of an adrenal medullary protein (synexin)that causes calcium-dependent aggregation of isolatedchromaffin granules. J Biol Chem. 1978;253:2858–2866.[22] Jimenez AJ, Maiuri P, Lafaurie-Janvore J, et al. ESCRTmachinery is required for plasma membrane repair.Science. 2014;343:1247136.[23] Scheffer LL, Sreetama SC, Sharma N, et al.Mechanism of Ca(2)(+)-triggered ESCRT assemblyand regulation of cell membrane repair. NatCommun. 2014;5:5646.COMMUNICATIVE & INTEGRATIVE BIOLOGY 165

Annexins:players of single cell wound healing and regeneration

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Annexins:players of single cell wound healing and regeneration

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