Li Zhou Nov 18th, 2017.

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1 Li Zhou Nov 18th, 2017

2 林圣彩 教授 Publications: 长江学者特聘教授，国家杰出青年基金获得者，博士生导师，厦门大学生命科学学院教授
长期致力于研究细胞生长和代谢稳态相关的信号转导通路及分子机制，迄今为止在国际主流刊物上发表SCI论文90余篇，其中以通讯作者在Nature、Science、 Nature Cell Biology、Cell Metabolism、Molecular Cell等杂志上上发表了一系列重要发现。 Publications: Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 2017. Metformin Activates AMPK through the Lysosomal Pathway. Cell Metab 2016. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab 2014. AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation. Cell Metab 2013. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science 2012.

3 Background

4 Background AMP exerts an initiating role for the assembly of the AMPK activating complex, by increasing the affinity of AMPK for AXIN that simultaneously binds LKB1. The resulting complex brings LKB1 to the vicinity of AMPK, promoting the phosphorylation of AMPK at Thr172. AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation. Cell Metab 2013.

5 Background The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab 2014.

6 Graphical Abstract

7 文章思路 Glucose deprivation activates AMPK via an AMP/ADP independent mechanism Glucose starvation activates AMPK by a lysosomal mechanism different from energy stress Absence of FBP defines a starvation signal for AMPK activation Aldolase is the receptor for FBP physically linking glucose deprivation to AMPK activation

8 葡萄糖饥饿可激活AMPK，但不依赖于AMP/ATP
1. Glucose deprivation activates AMPK via an AMP independent mechanism 葡萄糖饥饿可激活AMPK，但不依赖于AMP/ATP Ber: berberine, 黄连素, 线粒体抑制剂 饥饿4h

9 葡萄糖饥饿可激活AMPK，但不依赖于AMP/ATP
1. Glucose deprivation activates AMPK via an AMP independent mechanism 饥饿16h 葡萄糖饥饿可激活AMPK，但不依赖于AMP/ATP

10 1. Glucose deprivation activates AMPK via an AMP independent mechanism
Glc：葡萄糖 Gln：谷氨酰胺

11 1. Glucose deprivation activates AMPK via an AMP independent mechanism
Glc：葡萄糖 Gln：谷氨酰胺

12 1. Glucose deprivation activates AMPK via an AMP independent mechanism
RG：AMPK R531G mutant, 不能感应AMP/ATP

13 小结 细胞内碳源的缺失可通过传统的AMP/ADP依赖的途径激活AMPK 葡萄糖饥饿可激活AMPK，但不依赖于AMP/ATP
1. Glucose deprivation activates AMPK via an AMP independent mechanism 小结 细胞内碳源的缺失可通过传统的AMP/ADP依赖的途径激活AMPK 葡萄糖饥饿可激活AMPK，但不依赖于AMP/ATP

14 葡萄糖饥饿可能通过AXIN/LAMTOR1激活AMPK
2. Glucose starvation activates AMPK by a lysosomal mechanism different from energy stress 葡萄糖饥饿可能通过AXIN/LAMTOR1激活AMPK

15 2. Glucose starvation activates AMPK by a lysosomal mechanism different from energy stress
G2A: 不能被葡萄糖饥 饿激活的AMPK突变 S108A: 不能被激活剂 激活的AMPK突变 991: AMPK变构激活剂

16 2. Glucose starvation activates AMPK by a lysosomal mechanism different from energy stress
C433S: 不能在能量压力下激活AMPK的突变 A769882: AMPK变构激活剂

17 小结 ? 葡萄糖饥饿 葡萄糖饥饿通过溶酶体途径激活AMPK
2. Glucose starvation activates AMPK by a lysosomal mechanism different from energy stress 小结 葡萄糖饥饿 ? Lysosome Energy stress AMPK P 葡萄糖饥饿通过溶酶体途径激活AMPK

18 3. Absence of FBP defines a starvation signal for AMPK activation

19 3. Absence of FBP defines a starvation signal for AMPK activation
只有FBP可影响葡萄糖饥饿导致的AMPK激活

20 3. Absence of FBP defines a starvation signal for AMPK activation
只有FBP可影响葡萄糖饥饿导致的AMPK激活

21 3. Absence of FBP defines a starvation signal for AMPK activation

22 3. Absence of FBP defines a starvation signal for AMPK activation
葡萄糖饥饿时，回补FBP可抑制AMPK激活 SLO：溶血素O, 使细胞通透化

23 3. Absence of FBP defines a starvation signal for AMPK activation
葡萄糖饥饿时，回补FBP可抑制AMPK激活

24 3. Absence of FBP defines a starvation signal for AMPK activation
正常情况下，减少FBP可激活AMPK

25 小结 ? 葡萄糖饥饿 葡萄糖饥饿通过影响细胞内FBP含量激活AMPK
3. Absence of FBP defines a starvation signal for AMPK activation 小结 葡萄糖饥饿 ? P AMPK 葡萄糖饥饿通过影响细胞内FBP含量激活AMPK

26 ALDOA-C可能参与葡萄糖饥饿诱导的AMPK激活
4. Aldolase is the receptor for FBP physically linking glucose deprivation to AMPK activation FBP is a substrate for aldolases (ALDOA-C) and an allosteric activator of pyruvate kinase ALDOA-C可能参与葡萄糖饥饿诱导的AMPK激活

27 ALDOA-C可能参与葡萄糖饥饿诱导的AMPK激活
4. Aldolase is the receptor for FBP physically linking glucose deprivation to AMPK activation ALDOA-C可能参与葡萄糖饥饿诱导的AMPK激活

28 ALDOA-C可通过感应FBP含量调控AMPK激活复合体的形成
4. Aldolase is the receptor for FBP physically linking glucose deprivation to AMPK activation ALDOA-C可通过感应FBP含量调控AMPK激活复合体的形成

29 ALDOA-C只能通过FBP感应葡萄糖含量
4. Aldolase is the receptor for FBP physically linking glucose deprivation to AMPK activation ALDOA-C只能通过FBP感应葡萄糖含量

30 ALDOA-C调控AMPK激活依赖其对FBP的催化活性
4. Aldolase is the receptor for FBP physically linking glucose deprivation to AMPK activation ALDOA-C调控AMPK激活依赖其对FBP的催化活性 D34S：催化FBP向下反应的酶活降低的突变

31 ALDOA-C调控AMPK激活依赖其对FBP的催化活性
4. Aldolase is the receptor for FBP physically linking glucose deprivation to AMPK activation ALDOA-C调控AMPK激活依赖其对FBP的催化活性 D34S：催化FBP向下反应的酶活降低的突变

32 ALDOA-C调控AMPK激活依赖其与FBP的结合
4. Aldolase is the receptor for FBP physically linking glucose deprivation to AMPK activation ALDOA-C调控AMPK激活依赖其与FBP的结合 K230A：不能与FBP结合反应的突变

33 ALDOA-C调控AMPK激活依赖其与FBP的结合
4. Aldolase is the receptor for FBP physically linking glucose deprivation to AMPK activation ALDOA-C调控AMPK激活依赖其与FBP的结合 K230A：不能与FBP结合反应的突变

34 Conclusion

35 Thank You