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应激反应激酶MAPKAPK2/MAPKAPK3通过Beclin 1磷酸化激活饥饿诱导的自噬。

The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation.

作者信息

Wei Yongjie, An Zhenyi, Zou Zhongju, Sumpter Rhea, Su Minfei, Zang Xiao, Sinha Sangita, Gaestel Matthias, Levine Beth

机构信息

Center for Autophagy Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States.

Department of Chemistry and Biochemistry, North Dakota State University, Fargo, United States.

出版信息

Elife. 2015 Feb 18;4:e05289. doi: 10.7554/eLife.05289.

DOI:10.7554/eLife.05289
PMID:25693418
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4337728/
Abstract

Autophagy is a fundamental adaptive response to amino acid starvation orchestrated by conserved gene products, the autophagy (ATG) proteins. However, the cellular cues that activate the function of ATG proteins during amino acid starvation are incompletely understood. Here we show that two related stress-responsive kinases, members of the p38 mitogen-activated protein kinase (MAPK) signaling pathway MAPKAPK2 (MK2) and MAPKAPK3 (MK3), positively regulate starvation-induced autophagy by phosphorylating an essential ATG protein, Beclin 1, at serine 90, and that this phosphorylation site is essential for the tumor suppressor function of Beclin 1. Moreover, MK2/MK3-dependent Beclin 1 phosphorylation (and starvation-induced autophagy) is blocked in vitro and in vivo by BCL2, a negative regulator of Beclin 1. Together, these findings reveal MK2/MK3 as crucial stress-responsive kinases that promote autophagy through Beclin 1 S90 phosphorylation, and identify the blockade of MK2/3-dependent Beclin 1 S90 phosphorylation as a mechanism by which BCL2 inhibits the autophagy function of Beclin 1.

摘要

自噬是一种由保守基因产物自噬（ATG）蛋白精心调控的对氨基酸饥饿的基本适应性反应。然而，在氨基酸饥饿期间激活ATG蛋白功能的细胞信号仍未完全明确。在此，我们表明，p38丝裂原活化蛋白激酶（MAPK）信号通路中的两个相关应激反应激酶，即MAPKAPK2（MK2）和MAPKAPK3（MK3），通过在丝氨酸90位点磷酸化一种重要的ATG蛋白Beclin 1，正向调节饥饿诱导的自噬，且该磷酸化位点对于Beclin 1的肿瘤抑制功能至关重要。此外，Beclin 1的负调节因子BCL2在体外和体内均可阻断MK2/MK3依赖性的Beclin 1磷酸化（以及饥饿诱导的自噬）。这些发现共同揭示了MK2/MK3是通过Beclin 1 S90磷酸化促进自噬的关键应激反应激酶，并确定了阻断MK2/3依赖性的Beclin 1 S90磷酸化是BCL2抑制Beclin 1自噬功能的一种机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/408b/4337728/e7a99e6cd70a/elife05289f008.jpg
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