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.
Highlights
Liver kinase B1 (LKB1) is a tumor suppressor, metabolic sensor, and master modulator of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin complex1 activity, leading to the control of energy metabolism, cell polarity, cell survival, and proliferation (Corradetti et al, 2004; Alessi et al, 2006; Nakada et al, 2010)
We demonstrated the intermingled essential and systemic roles of Lkb1 and autophagy in the maintenance of mouse homeostasis and survival via conditional whole-body deletion of Stk11 and Atg7 in adult mice (Figure 6)
We found that acute Lkb1 loss led to damaged intestinal epithelium barrier and increased infection, and alteration in metabolic pathways necessary for maintaining host homeostasis, which was partially rescued by autophagy activation via inhibiting p53 induction
Summary
Liver kinase B1 (LKB1) is a tumor suppressor, metabolic sensor, and master modulator of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin complex (mTORC1) activity, leading to the control of energy metabolism, cell polarity, cell survival, and proliferation (Corradetti et al, 2004; Alessi et al, 2006; Nakada et al, 2010). Serum metabolomics profiling analysis showed that acute short-term deletion of Atg or Stk, respectively, significantly decreased the levels of most essential and nonessential amino acids and some metabolites involved in the tricarboxylic acid (TCA) cycle, urea cycle, and glycolysis. This phenotype was further enhanced in mice with concurrent deletions of Atg and Stk.
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