title: Dynamic involvement of ATG5 in cellular stress responses.
abstract: Autophagy maintains cell and tissue homeostasis through catabolic degradation. To better delineate the in vivo function for autophagy in adaptive responses to tissue injury, we examined the impact of compromised autophagy in mouse submandibular glands (SMGs) subjected to main excretory duct ligation. Blocking outflow from exocrine glands causes glandular atrophy by increased ductal pressure. Atg5(f/-);Aqp5-Cre mice with salivary acinar-specific knockout (KO) of autophagy essential gene Atg5 were generated. While duct ligation induced autophagy and the expression of inflammatory mediators, SMGs in Atg5(f/-);Aqp5-Cre mice, before ligation, already expressed higher levels of proinflammatory cytokine and Cdkn1a/p21 messages. Extended ligation period resulted in the caspase-3 activation and acinar cell death, which was delayed by Atg5 knockout. Moreover, expression of a set of senescence-associated secretory phenotype (SASP) factors was elevated in the post-ligated glands. Dysregulation of cell-cycle inhibitor CDKN1A/p21 and activation of senescence-associated β-galactosidase were detected in the stressed SMG duct cells. These senescence markers peaked at day 3 after ligation and partially resolved by day 7 in post-ligated SMGs of wild-type (WT) mice, but not in KO mice. The role of autophagy-related 5 (ATG5)-dependent autophagy in regulating the tempo, duration and magnitude of cellular stress responses in vivo was corroborated by in vitro studies using MEFs lacking ATG5 or autophagy-related 7 (ATG7) and autophagy inhibitors. Collectively, our results highlight the role of ATG5 in the dynamic regulation of ligation-induced cellular senescence and apoptosis, and suggest the involvement of autophagy resolution in salivary repair.
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Lin
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: S-M
authors.initials: SM
authors.lastname: Lin
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chung
authors.affiliation: Division of Comparative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Vonderfecht
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, MO, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Camden
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Will Rogers Institute Pulmonary Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Flodby
authors.affiliation: 1] Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Will Rogers Institute Pulmonary Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA [2] Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Borok
authors.affiliation: Department of Nutritional Sciences, The University of Arizona, Tucson, AZ, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Limesand
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Mizushima
authors.affiliation: 1] Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA, USA [2] Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Ann
mesh_terms: D061354:Acinar Cells / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D016922:Cellular Senescence; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008026:Ligation; D008262:Macrophage Activation; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008954:Models, Biological; D009928:Organ Specificity; D010641:Phenotype; D013312:Stress, Physiological; D013363:Submandibular Gland / Q000378:metabolism
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D016207:Cytokines; D018836:Inflammation Mediators; D008869:Microtubule-Associated Proteins