The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression.
LKB1 is a serine/threonine kinase that directly activates the energy sensor AMP-activated protein kinase (AMPK) in response to bioenergetic stress, and mainly acts as a tumor suppressor that controls cell polarity and proliferation. Although LKB1 is expressed in multiple tissues including the thymus and the spleen, its roles in T-cell development and function remain unknown. Here, we show that T-cell-specific deletion of LKB1 resulted in reduced survival of double-positive (DP) thymocytes and impaired generation of both CD4 and CD8 single-positive thymocytes. Disruption of LKB1 not only prevented the activation of AMPK but also impaired the expression of anti-apoptotic protein Bcl-XL. Importantly, ectopic expression of either Bcl-XL or the constitutively active AMPK mutant significantly rescued DP thymocytes from LKB1 deficiency-induced cell death. Moreover, ectopic expression of the constitutively active AMPK mutant was found to restore the expression of Bcl-XL in LKB1-deficient DP thymocytes. These findings identify LKB1 as a critical factor for the survival of DP thymocytes through regulation of AMPK activation and Bcl-XL expression.
Cao
Yonghao
Y
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Li
Hai
H
Liu
Haifeng
H
Zheng
Chao
C
Ji
Hongbin
H
Liu
Xiaolong
X
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
C494812:Bcl2l1 protein, mouse; D051020:bcl-X Protein; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases