AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
Joungmok Kim, Mondira Kundu, Benoit Viollet and Kun-Liang Guan
Nature Cell Biology 13, 132–141 (2011)
Presenter: Tai-Ying Kao
Date/Time: 2012/05/31 16:10 -17:00
Commentator: Dr. Chi-Wu Chiang
Location: Room 602, Med College Building
Background:
Autophagy is a process by which components of the cell are degraded to maintain essential activity and
viability in response to nutrient limitation. The molecular mechanism of autophagy has been revealed by
genetic analyses performed in yeast, in which 31 autophagy-related ATG genes have been identified so far.
Among the components of this machinery, the ATG1 kinase, which forms a complex with ATG13 and
ATG17, is a key regulator in autophagy initiation. Mammals have ATG1 homologues, Ulk1 and Ulk2, and
the mammalian counterparts of ATG13 and ATG17 are reported as mATG13 and FIP200, respectively.
Furthermore, autophagy is promoted by AMP-activated protein kinase (AMPK), which is a key energy
sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited
by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor
and nutrient signals. Recent studies have shown a physical interaction between Ulk1 and AMPK, and Ulk1
is negatively regulated by the mTOR. However, the mechanism underlying Ulk1 regulation is largely
unknown, although a modest Ulk1 activation induced by nutrient starvation has been reported.
Objective/Hypothesis:
To investigate how AMPK and mTORC1 regulate autophagy through coordinated phosphorylation of
Ulk1.
Results:
First, the authors demonstrate that glucose starvation may induce Ulk1 phosphorylation and was
suppressed by inhibition of AMPK with compound C or by co-expression of the AMPKα kinase-dead (DN)
mutant. Then the authors found that AMPK phosphorylated the serine/threonine-rich domain (S/T domain)
of Ulk1, and further deletion/mutation analyses identified Ser 317 and Ser 777 as the major AMPK
phosphorylation sites. Next, the authors found that under nutrient sufficiency, high mTOR activity disrupts
the interaction between Ulk1 and AMPK through direct phosphorylation of Ulk1 Ser 757, thereby
preventing Ulk1 activation by AMPK. Under glucose starvation, the activated AMPK inhibits mTORC1 to
relieve Ser 757 phosphorylation, leading to Ulk1–AMPK interaction. AMPK then phosphorylates Ulk1 on
Ser 317 and Ser 777, activates Ulk1 kinase, and eventually leads to autophagy induction.
Conclusion:
The identification of Ulk1 as a direct target of mTORC1 and AMPK represents a significant step
towards the understating how cellular nutrient sensor/integrator regulates autophagy machinery.
Reference :
Lee, J. W., Park, S., Takahashi, Y. & Wang, H. G. The association of AMPK with ULK1 regulates
autophagy. PLoS One 5, e15394 (2010).