Drosophila salt-inducible kinase (SIK) regulates starvation resistance through cAMP-response element-binding protein (CREB)-regulated transcription coactivator (CRTC).
Salt-inducible kinase (SIK), one of the AMP-activated kinase (AMPK)-related kinases, has been suggested to play important functions in glucose homeostasis by inhibiting the cAMP-response element-binding protein (CREB)-regulated transcription coactivator (CRTC). To examine the role of SIK in vivo, we generated Drosophila SIK mutant and found that the mutant flies have higher amounts of lipid and glycogen stores and are resistant to starvation. Interestingly, SIK transcripts are highly enriched in the brain, and we found that neuron-specific expression of exogenous SIK fully rescued lipid and glycogen storage phenotypes as well as starvation resistance of the mutant. Using genetic and biochemical analyses, we demonstrated that CRTC Ser-157 phosphorylation by SIK is critical for inhibiting CRTC activity in vivo. Furthermore, double mutants of SIK and CRTC became sensitive to starvation, and the Ser-157 phosphomimetic mutation of CRTC reduced lipid and glycogen levels in the SIK mutant, suggesting that CRTC mediates the effects of SIK signaling. Collectively, our results strongly support the importance of the SIK-CRTC signaling axis that functions in the brain to maintain energy homeostasis in Drosophila.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 335 Gwahangno, Yuseong-Gu, Daejeon 305-701, Republic of Korea.
Sekyu
S
Choi
Wonho
W
Kim
Jongkyeong
J
Chung
D000818:Animals; D000242:Cyclic AMP; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D015971:Gene Expression Regulation, Enzymologic; D009154:Mutation; D009928:Organ Specificity / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements / Q000502:physiology*; D015398:Signal Transduction; D013217:Starvation / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C578084:CRTC protein, Drosophila; D029721:Drosophila Proteins; D014157:Transcription Factors; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases