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

Elife. 2020 Nov 25:9:e62377. doi: 10.7554/eLife.62377.

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.

Keywords: Atg7; LKB1; autophagy; cell biology; host homeostasis; infectious disease; intestinal epithelium barrier; microbiology; mouse; p53.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Autophagy / physiology*
  • Autophagy-Related Protein 7 / genetics
  • Autophagy-Related Protein 7 / metabolism*
  • Epithelial Cells
  • Gene Deletion
  • Gene Expression Regulation / physiology
  • Homeostasis / genetics
  • Homeostasis / physiology*
  • Intestinal Mucosa / cytology
  • Mice
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Survival
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Atg7 protein, mouse
  • Tumor Suppressor Protein p53
  • Protein Serine-Threonine Kinases
  • Stk11 protein, mouse
  • AMP-Activated Protein Kinases
  • Autophagy-Related Protein 7