4.7 Article

ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program

期刊

EMBO REPORTS
卷 22, 期 9, 页码 -

出版社

WILEY
DOI: 10.15252/embr.202051806

关键词

acinar-ductal metaplasia; BHLHA15; plasticity; RAB5; spasmolytic polypeptide-expressing metaplasia

资金

  1. AITAC of the Washington University Digestive Disease Center [DDRCC: P30 DK052574]
  2. NIH Shared Instrumentation Grant [S10RR0227552]
  3. Children's Discovery Institute of Washington University
  4. St. Louis Children's Hospital [CDI-CORE-2015-505, CDI-CORE-2019-813]
  5. Foundation for Barnes-Jewish Hospital [3770]
  6. Siteman Cancer Center [P30CA091842]
  7. NIH NCI [F31CA236506-01, T32-CA009547]
  8. Philip and Sima Needleman Student Fellowship in Regenerative Medicine [5T32GM007067-43]
  9. Siteman Cancer Center Cancer Pathway Program [P30 CA091842, T32CA113275]
  10. Washington University Biology Summer Undergraduate Research Fellowship Program (BioSURF)
  11. Department of Defense, through the PRCRP program [W81XWH2010630, T32-DK007130]
  12. Digestive Disease Research Core Centers Pilot and Feasibility Grant [P30 DK05257, NIH R21 AI156236]
  13. American Gastroenterological Association [AGA2021-5101]
  14. National Institutes of Health (NIH) [GM007067]
  15. Philip and Sima Needleman Student Fellowship in Regenerative Medicine
  16. National Institute of Diabetes and Digestive and Kidney Diseases [R21 DK111369, R01DK094989, R01DK105129, R01DK110406 R01120680]
  17. National Institutes of Health National Cancer Institute [P30 CA09182, R01 CA239645, R01 CA246208]
  18. BETRNet [U54 CA163060]
  19. U.S. Department of Defense (DOD) [W81XWH2010630] Funding Source: U.S. Department of Defense (DOD)

向作者/读者索取更多资源

ATF3 and RAB7B are upregulated in the early Stage 1 of paligenosis to help cells induce autophagic and lysosomal mechanisms. Atf3(-/-) mice fail to induce autophagic and lysosomal vesicles, leading to increased cell death. The evolutionarily conserved ATF3 gene orchestrates early paligenotic autodegradative events.
Differentiated cells across multiple species and organs can re-enter the cell cycle to aid in injury-induced tissue regeneration by a cellular program called paligenosis. Here, we show that activating transcription factor 3 (ATF3) is induced early during paligenosis in multiple cellular contexts, transcriptionally activating the lysosomal trafficking gene Rab7b. ATF3 and RAB7B are upregulated in gastric and pancreatic digestive-enzyme-secreting cells at the onset of paligenosis Stage 1, when cells massively induce autophagic and lysosomal machinery to dismantle differentiated cell morphological features. Their expression later ebbs before cells enter mitosis during Stage 3. Atf3(-/-) mice fail to induce RAB7-positive autophagic and lysosomal vesicles, eventually causing increased death of cells en route to Stage 3. Finally, we observe that ATF3 is expressed in human gastric metaplasia and during paligenotic injury across multiple other organs and species. Thus, our findings indicate ATF3 is an evolutionarily conserved gene orchestrating the early paligenotic autodegradative events that must occur before cells are poised to proliferate and contribute to tissue repair.

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