Dynamic involvement of ATG5 in cellular stress responses

H. H. Lin, S. M. Lin, Y. Chung, S. Vonderfecht, J. M. Camden, P. Flodby, Z. Borok, Kirsten Limesand, N. Mizushima, D. K. Ann

Research output: Contribution to journalArticle

12 Citations (Scopus)

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. Atg5f/- ;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 Atg5f/ -;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 ß-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.

Original languageEnglish (US)
Article numbere1478
JournalCell Death and Disease
Volume5
Issue number10
DOIs
StatePublished - Jan 1 2014

Fingerprint

Autophagy
Ligation
Submandibular Gland
Galactosidases
Exocrine Glands
Acinar Cells
Cell Aging
Essential Genes
Knockout Mice
Caspase 3
Atrophy
Cell Cycle
Homeostasis
Cell Death
Apoptosis
Cytokines
Phenotype

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Lin, H. H., Lin, S. M., Chung, Y., Vonderfecht, S., Camden, J. M., Flodby, P., ... Ann, D. K. (2014). Dynamic involvement of ATG5 in cellular stress responses. Cell Death and Disease, 5(10), [e1478]. https://doi.org/10.1038/cddis.2014.428

Dynamic involvement of ATG5 in cellular stress responses. / Lin, H. H.; Lin, S. M.; Chung, Y.; Vonderfecht, S.; Camden, J. M.; Flodby, P.; Borok, Z.; Limesand, Kirsten; Mizushima, N.; Ann, D. K.

In: Cell Death and Disease, Vol. 5, No. 10, e1478, 01.01.2014.

Research output: Contribution to journalArticle

Lin, HH, Lin, SM, Chung, Y, Vonderfecht, S, Camden, JM, Flodby, P, Borok, Z, Limesand, K, Mizushima, N & Ann, DK 2014, 'Dynamic involvement of ATG5 in cellular stress responses', Cell Death and Disease, vol. 5, no. 10, e1478. https://doi.org/10.1038/cddis.2014.428
Lin HH, Lin SM, Chung Y, Vonderfecht S, Camden JM, Flodby P et al. Dynamic involvement of ATG5 in cellular stress responses. Cell Death and Disease. 2014 Jan 1;5(10). e1478. https://doi.org/10.1038/cddis.2014.428
Lin, H. H. ; Lin, S. M. ; Chung, Y. ; Vonderfecht, S. ; Camden, J. M. ; Flodby, P. ; Borok, Z. ; Limesand, Kirsten ; Mizushima, N. ; Ann, D. K. / Dynamic involvement of ATG5 in cellular stress responses. In: Cell Death and Disease. 2014 ; Vol. 5, No. 10.
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