Journal article
BECLIN1 is essential for intestinal homeostasis involving autophagy-independent mechanisms through its function in endocytic trafficking
Sharon Tran, Juliani Juliani, Tiffany J Harris, Marco Evangelista, Julian Ratcliffe, Sarah L Ellis, David Baloyan, Camilla M Reehorst, Rebecca Nightingale, Ian Y Luk, Laura J Jenkins, Sonia Ghilas, Marina H Yakou, Chantelle Inguanti, Chad Johnson, Michael Buchert, James C Lee, Peter de Cruz, Kinga Duszyc, Paul A Gleeson Show all
Communications Biology | Nature Portfolio | Published : 2024
Abstract
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 regula..
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Awarded by Australian Research Council
Awarded by National Health and Medical Research Council
Awarded by Victorian Cancer Agency
Awarded by Francis Crick Institute from Cancer Research UK
Awarded by UK Medical Research Council
Awarded by Wellcome Trust
Funding Acknowledgements
We thank Professor Joan Heath and Dr. Karen Doggett for providing the B6.Cg-Ndor1Tg(UBC-cre/ERT2)1Ejb/1 J or UBC-Cre-ERT2 mice (Walter and Eliza Hall Institute, Melbourne, VIC, Australia). We acknowledge scholarship support for S.T. (La Trobe University Research Training Program Scholarship), L.J.J. (La Trobe University Australian Postgraduate Award), and J.J. (La Trobe Graduate Research Scholarship and Full Fee Research Scholarship). We are grateful to the Australian Research Council for grant support (E.F.L., W.D.F., J.M.M., DP190102612; P.A.G., DP160102394) and to the National Health and Medical Research Council (J.M.M., 1046092; K.D., A.S.Y., 2010704, 1136592), the Victorian Cancer Agency (E.F.L., MCRF19045) for fellowship support. J.C.L. is a Lister Institute Prize Fellow and supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2219), the UK Medical Research Council (CC2219), and the Wellcome Trust (CC2219).