title: Inhibition or ablation of transglutaminase 2 impairs astrocyte migration.
abstract: Astrocytes play numerous complex roles that support and facilitate the function of neurons. Further, when there is an injury to the central nervous system (CNS) they can both facilitate or ameliorate functional recovery depending on the location and severity of the injury. When a CNS injury is relatively severe a glial scar is formed, which is primarily composed of astrocytes. The glial scar can be both beneficial, by limiting inflammation, and detrimental, by preventing neuronal projections, to functional recovery. Thus, understanding the processes and proteins that regulate astrocyte migration in response to injury is still of fundamental importance. One protein that is likely involved in astrocyte migration is transglutaminase 2 (TG2); a multifunctional protein expressed ubiquitously throughout the brain. Its functions include transamidation and GTPase activity, among others, and previous studies have implicated TG2 as a regulator of migration. Therefore, we examined the role of TG2 in primary astrocyte migration subsequent to injury. Using wild type or TG2-/-astrocytes, we manipulated the different functions and conformation of TG2 with novel irreversible inhibitors or mutant versions of the protein. Results showed that both inhibition and ablation of TG2 in primary astrocytes significantly inhibit migration. Additionally, we show that the deficiency in migration caused by deletion of TG2 can only be rescued with the native protein and not with mutants. Finally, the addition of TGFβ rescued the migration deficiency independent of TG2. Taken together, our study shows that transamidation and GTP/GDP-binding are necessary for inhibiting astrocyte migration and it is TGFβ independent.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Monteagudo
authors.affiliation: Department of Anesthesiology, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Changyi
authors.initials: C
authors.lastname: Ji
authors.affiliation: Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Akbar
authors.affiliation: Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Keillor
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, USA; Department of Anesthesiology, University of Rochester, Rochester, NY 14642, USA. Electronic address: gail_johnsonvoll@urmc.rochester.edu.
authors.forename: Gail V W
authors.initials: GVW
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D008810:Mice, Inbred C57BL; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D016212:Transforming Growth Factor beta / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Astrocytes; Migration; TGFβ; Transamidation; Transglutaminase 2