Abstract
Autophagy is a catabolic process to degrade both damaged organelles and aggregated proteins in somatic cells. We have recently identified that autophagy is an executor for mitochondrial homeostasis in embryonic stem cell (ESC), and thus contribute to stemness regulation. However, the regulatory and functional mechanisms of autophagy in ESC are still largely unknown. Here we have shown that activation of ULK1 by AMPK is essential for ESC self-renewal and pluripotency. Dysfunction of Ulk1 decreases the autophagic flux in ESC, leading to compromised self-renewal and pluripotency. These defects can be rescued by reacquisition of wild-type ULK1 and ULK1(S757A) mutant, but not ULK1(S317A, S555A and S777A) and kinase dead ULK1(K46I) mutant. These data indicate that phosphorylation of ULK1 by AMPK, but not mTOR, is essential for stemness regulation in ESC. The findings highlight a critical role for AMPK-dependent phosphorylation of ULK1 pathway to maintain ESC self-renewal and pluripotency.
Highlights
Autophagy is a catabolic process to degrade both damaged organelles and aggregated proteins in somatic cells
Recently, we have demonstrated that ATG3-dependent autophagy plays critical roles in maintaining the embryonic stem cell (ESC) stemness
Five ATG1 homologous have been identified as ULK1, ULK2, ULK3, ULK4, and STK36
Summary
Autophagy is a catabolic process to degrade both damaged organelles and aggregated proteins in somatic cells. Dysfunction of Ulk[1] decreases the autophagic flux in ESC, leading to compromised self-renewal and pluripotency. These defects can be rescued by reacquisition of wild-type ULK1 and ULK1(S757A) mutant, but not ULK1 (S317A, S555A and S777A) and kinase dead ULK1(K46I) mutant. In contrast to the function study of autophagy in somatic cells, the role of autophagy in the regulation of stemness regulation; how the ESC maintain their self-renewal and pluripotency through metabolic regulation is largely unknown. We have identified the catabolic process autophagy as an executor to degrade the mitochondria in ESC, and maintain their mitochondrial homeostasis. As a critical autophagyinitiating kinase, how ULK1 is regulated, and contribute to ESC stemness modulation, is unclear
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