Dynamic involvement of ATG5 in cellular stress responses

• Published in: Cell death & disease Vol. 5; no. 10; p. e1478
• Main Authors: Lin, H H, Lin, S-M, Chung, Y, Vonderfecht, S, Camden, J M, Flodby, P, Borok, Z, Limesand, K H, Mizushima, N, Ann, D K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-10-2014; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/80/509; 631/80/82/39; 631/80/86; Acinar Cells - metabolism; Animals; Antibodies; Apoptosis; Autophagy; Autophagy-Related Protein 5; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cellular Senescence; Cytokines - genetics; Cytokines - metabolism; Immunology; Inflammation Mediators - metabolism; Life Sciences; Ligation; Macrophage Activation; Mice, Knockout; Microtubule-Associated Proteins - metabolism; Models, Biological; Organ Specificity; Original; original-article; Phenotype; Stress, Physiological; Submandibular Gland - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.428

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.