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

  1. Khoosheh Khayati
  2. Vrushank Bhatt
  3. Zhixian Sherrie Hu
  4. Sajid Fahumy
  5. Xuefei Luo
  6. Jessie Yanxiang Guo  Is a corresponding author
  1. Rutegrs Cancer Institute of New Jersey, United States
  2. Rutgers Cancer Institute of New Jersey, 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 access 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Khoosheh Khayati

    Medicine, Rutegrs Cancer Institute of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2424-837X
  2. Vrushank Bhatt

    Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Zhixian Sherrie Hu

    Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sajid Fahumy

    Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xuefei Luo

    Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jessie Yanxiang Guo

    Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick, United States
    For correspondence
    yanxiang@cinj.rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9212-7954

Funding

National Cancer Institute (R01CA237347-01A1)

  • Jessie Yanxiang Guo

Mistletoe Research Fellowship (Predoctoral fellowship)

  • Vrushank Bhatt

National Cancer Institute (K22 CA190521)

  • Jessie Yanxiang Guo

American Cancer Society (134036-RSG-19-165-01-TBG)

  • Jessie Yanxiang Guo

GO2 Foundation for Lung Cancer (Young Innovators Team Awards)

  • Jessie Yanxiang Guo

Lung Cancer Research Foundation (Research Grant)

  • Jessie Yanxiang Guo

New Jersey Commission on Cancer Research (DFHS18PPC021,Postdoc fellowship)

  • Khoosheh Khayati

New Jersey Commission on Cancer Research (DCHS19PPC013,Predoctoral fellowship)

  • Vrushank Bhatt

Rutgers Busch Biomedical grant (Research Grant)

  • Jessie Yanxiang Guo

Cox Foundation for Cancer Research (Predoctoral fellowship)

  • Vrushank Bhatt

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#I15-074) of the Rutgers University.

Reviewing Editor

  1. Noboru Mizushima, The University of Tokyo, Japan

Publication history

  1. Received: August 22, 2020
  2. Accepted: November 24, 2020
  3. Accepted Manuscript published: November 25, 2020 (version 1)
  4. Version of Record published: December 3, 2020 (version 2)

Copyright

© 2020, Khayati et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Khoosheh Khayati
  2. Vrushank Bhatt
  3. Zhixian Sherrie Hu
  4. Sajid Fahumy
  5. Xuefei Luo
  6. Jessie Yanxiang Guo
(2020)
Autophagy compensates for Lkb1 loss to maintain adult mice homeostasis and survival
eLife 9:e62377.
https://doi.org/10.7554/eLife.62377

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