title: Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis.
abstract: Astrocytes are known to facilitate repair following brain injury; however, little is known about how injured astrocytes repair themselves. Repair of cell membrane injury requires Ca(2+)-triggered vesicle exocytosis. In astrocytes, lysosomes are the main Ca(2+)-regulated exocytic vesicles. Here we show that astrocyte cell membrane injury results in a large and rapid calcium increase. This triggers robust lysosome exocytosis where the fusing lysosomes release all luminal contents and merge fully with the plasma membrane. In contrast to this, receptor stimulation produces a small sustained calcium increase, which is associated with partial release of the lysosomal luminal content, and the lysosome membrane does not merge into the plasma membrane. In most cells, lysosomes express the synaptotagmin (Syt) isoform Syt VII; however, this isoform is not present on astrocyte lysosomes and exogenous expression of Syt VII on lysosome inhibits their exocytosis. Deletion of one of the most abundant Syt isoform in astrocyte--Syt XI--suppresses astrocyte lysosome exocytosis. This identifies lysosome as Syt XI-regulated exocytic vesicle in astrocytes. Further, inhibition of lysosome exocytosis (by Syt XI depletion or Syt VII expression) prevents repair of injured astrocytes. These results identify the lysosomes and Syt XI as the sub-cellular and molecular regulators, respectively of astrocyte cell membrane repair.
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Sreetama
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Takano
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nedergaard
authors.affiliation: Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Simon
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC, USA.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue NW, Washington, DC, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Jaiswal
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005089:Exocytosis; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D050857:Synaptotagmins / Q000378:metabolism*
chemical_list: C494266:Syt11 protein, mouse; D050857:Synaptotagmins