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核内转移的ACSS2促进溶酶体生物合成和自噬相关的基因转录

发布时间:2017-10-23 10:24 |  点击次数:

营养压力(即限制乙酰辅酶A从葡萄糖转化或乙酸酯获取),引起ACSS2在S659位点磷酸化并向核内转移。与TFEB结合的ACSS2会在溶酶体和自噬相关基因启动子区域与染色体结合,促进吸收、利用组蛋白乙酰化循环释放的乙酸脂合成乙酰辅酶A,后者驱动H3组蛋白乙酰化并活化上述基因表达。上述过程促进溶酶体生长,自噬以及脑肿瘤生长。



Figure 1. ACSS2 S659 Phosphorylation by AMPK Induces Nuclear Translocation of ACSS2
 
(B–G) Immunoblot analyses were performed with the indicated antibodies.
 
  • U87 cells were deprived of glucose for 1 hr. Immunofluorescent analyses were performed with an anti-ACSS2 antibody. DAPI (blue) was used to stain the nuclei.
 
  • U87 cells were deprived of glucose for 1 hr. Total cell lysates and cytosolic and nuclear fractions were prepared. Activation of AMPK is reflected by AMPKa T172 phosphorylation.
 
  • WT and AMPKa1 and AMPKa2 double-knockout (DKO) MEFs were treated with 2-DG (25 mM) for the indicated periods. Total cell lysates and cytosolic and nuclear fractions were prepared.
 
  • U87 cells were deprived of glucose for 10 min. Immunoprecipitation with an anti-AMPKa antibody was performed.
 
  • Purified AMPK was mixed with the indicated bacterially purified His-ACSS2 proteins and [g-32P] ATP in the presence or absence of AMP (100 mM). Auto-radiographic analysis was performed.
 
  • U87 cells expressing the indicated FLAG-ACSS2 proteins were deprived of glucose for 1 hr. Immunoprecipitation with an anti-FLAG antibody was performed. Activation of AMPK is reflected by its substrate acetyl-CoA carboxylase (ACC) S79 phosphorylation.
 
  • WT and AMPKa1/2 DKO MEFs were deprived of glucose for 1 hr. Total cell lysates were prepared.
 
U87 cells expressing the indicated FLAG-ACSS2 proteins were deprived of glucose for 1 hr. Immunofluorescent analyses were performed with an anti-FLAG antibody. The percentage of nuclear ACSS in 20 cells in each group was quantitated (right) using ImageJ. A two-tailed Student’s t test was used. *p < 0.001.

 
原文参考链接
 

Li et al., 2017, Molecular Cell 66, 1–14 June 1, 2017 ª 2017 Elsevier Inc.

 
http://dx.doi.org/10.1016/j.molcel.2017.04.026
Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis
and Autophagy


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