BECLIN1 is essential for intestinal homeostasis involving autophagy-independent mechanisms through its function in endocytic trafficking.

Autor: Tran S; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Juliani J; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia.; Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia.; La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia., Harris TJ; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Evangelista M; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Ratcliffe J; Bioimaging Platform, La Trobe University, Bundoora, VIC, Australia., Ellis SL; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Baloyan D; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Reehorst CM; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Nightingale R; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Luk IY; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Jenkins LJ; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Ghilas S; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Yakou MH; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Inguanti C; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Johnson C; Bioimaging Platform, La Trobe University, Bundoora, VIC, Australia., Buchert M; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Lee JC; Genetic Mechanisms of Disease Laboratory, the Francis Crick Institute, London, United Kingdom.; Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, University College London, London, United Kingdom., De Cruz P; Department of Gastroenterology, Austin Health, Melbourne, VIC, Australia.; Department of Medicine, Austin Academic Centre, The University of Melbourne, Melbourne, VIC, Australia., Duszyc K; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, QLD, Australia., Gleeson PA; Department of Biochemistry and Pharmacology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, Australia., Kile BT; Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., Mielke LA; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Yap AS; Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, QLD, Australia., Mariadason JM; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia., Fairlie WD; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia. Doug.Fairlie@onjcri.org.au.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia. Doug.Fairlie@onjcri.org.au.; Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia. Doug.Fairlie@onjcri.org.au.; La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia. Doug.Fairlie@onjcri.org.au., Lee EF; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia. Erinna.Lee@latrobe.edu.au.; School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia. Erinna.Lee@latrobe.edu.au.; Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia. Erinna.Lee@latrobe.edu.au.; La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia. Erinna.Lee@latrobe.edu.au.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2024 Feb 20; Vol. 7 (1), pp. 209. Date of Electronic Publication: 2024 Feb 20.
DOI: 10.1038/s42003-024-05890-7
Abstrakt: Autophagy-related genes have been closely associated with intestinal homeostasis. BECLIN1 is a component of Class III phosphatidylinositol 3-kinase complexes that orchestrate autophagy initiation and endocytic trafficking. Here we show intestinal epithelium-specific BECLIN1 deletion in adult mice leads to rapid fatal enteritis with compromised gut barrier integrity, highlighting its intrinsic critical role in gut maintenance. BECLIN1-deficient intestinal epithelial cells exhibit extensive apoptosis, impaired autophagy, and stressed endoplasmic reticulum and mitochondria. Remaining absorptive enterocytes and secretory cells display morphological abnormalities. Deletion of the autophagy regulator, ATG7, fails to elicit similar effects, suggesting additional novel autophagy-independent functions of BECLIN1 distinct from ATG7. Indeed, organoids derived from BECLIN1 KO mice show E-CADHERIN mislocalisation associated with abnormalities in the endocytic trafficking pathway. This provides a mechanism linking endocytic trafficking mediated by BECLIN1 and loss of intestinal barrier integrity. Our findings establish an indispensable role of BECLIN1 in maintaining mammalian intestinal homeostasis and uncover its involvement in endocytic trafficking in this process. Hence, this study has important implications for our understanding of intestinal pathophysiology.
(© 2024. The Author(s).)
Databáze: MEDLINE
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