Autophagy compensates for Lkb1 loss to maintain adult mice homeostasis and survival

Author:

Khayati Khoosheh1ORCID,Bhatt Vrushank1,Hu Zhixian Sherrie1,Fahumy Sajid1,Luo Xuefei1,Guo Jessie Yanxiang123ORCID

Affiliation:

1. Rutgers Cancer Institute of New Jersey, New Brunswick, United States

2. Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, United States

3. Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, United States

Abstract

Liver kinase B1 (LKB1), also known as serine/threonine kinase 11 (STK11) is the major energy sensor for cells to respond to metabolic stress. Autophagy degrades and recycles proteins, macromolecules, and organelles for cells to survive starvation. To assess the role and cross-talk between autophagy and Lkb1 in normal tissue homeostasis, we generated genetically engineered mouse models where we can conditionally delete Stk11 and autophagy essential gene, Atg7, respectively or simultaneously, throughout the adult mice. We found that Lkb1 was essential for the survival of adult mice, and autophagy activation could temporarily compensate for the acute loss of Lkb1 and extend mouse life span. We further found that acute deletion of Lkb1 in adult mice led to impaired intestinal barrier function, hypoglycemia, and abnormal serum metabolism, which was partly rescued by the Lkb1 loss-induced autophagy upregulation via inhibiting p53 induction. Taken together, we demonstrated that autophagy and Lkb1 work synergistically to maintain adult mouse homeostasis and survival.

Funder

National Cancer Institute

American Cancer Society

GO2 Foundation for Lung Cancer

Lung Cancer Research Foundation

New Jersey Commission on Cancer Research

Rutgers Busch Biomedical Grant

Cox Foundation for Cancer Research

Mistletoe Research Fellowship

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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