BAG3 promotes autophagy and glutaminolysis via stabilizing glutaminase
BAG3 promotes autophagy and glutaminolysis via stabilizing glutaminase
复制标题
BAG3 通过稳定谷氨酰胺酶促进自噬和谷氨酰胺分解
DOI：
10.1038/s41419-019-1504-6
复制
发表时间：
2019-03-25
影响因子：
9
通讯作者：
Wang, Hua-Qin
中科院分区：
文献类型：
--
作者：
Zhao, Song;Wang, Jia-Mei;Wang, Hua-Qin
Bcl-2相关凋亡基因3（BAG 3）是一种重要的分子，通过多种机制维持癌细胞的致癌特征。BAG 3的重要功能之一是参与选择性巨自噬/自噬，近年来引起了人们的广泛关注。然而，BAG 3调节自噬的机制尚未得到很好的定义。在这里，我们描述了BAG 3通过促进谷氨酰胺消耗和谷氨酰胺分解来增强自噬。谷氨酰胺分解起始于谷氨酰胺通过谷氨酰胺酶（GLS）的脱氨基作用，由此在线粒体中产生谷氨酸和氨。目前的研究表明，BAG 3通过抑制其与SIRT 5的相互作用来稳定GLS，从而阻碍其在Lys 158和Lys 164位点的去琥珀酰化。作为一种潜在的分子机制，我们证明BAG 3与GLS相互作用并降低SIRT 5表达。目前的研究还表明，琥珀酰在Lys 158和Lys 164位点的占领禁止其Lys 48连接的泛素化，从而防止其随后的蛋白酶体降解。总的来说，目前的研究表明，BAG 3通过稳定GLS和促进β-氨基糖苷酶分解来增强自噬。这项研究首次报道了琥珀酰化与泛素化竞争调节蛋白酶体GLS降解。
Bcl-2 associated athanogene 3 (BAG3) is an important molecule that maintains oncogenic features of cancer cells via diverse mechanisms. One of the important functions assigned to BAG3 is implicated in selective macroautophagy/autophagy, which attracts much attention recently. However, the mechanism underlying regulation of autophagy by BAG3 has not been well defined. Here, we describe that BAG3 enhances autophagy via promotion of glutamine consumption and glutaminolysis. Glutaminolysis initiates with deamination of glutamine by glutaminase (GLS), by which yields glutamate and ammonia in mitochondria. The current study demonstrates that BAG3 stabilizes GLS via prohibition its interaction with SIRT5, thereby hindering its desuccinylation at Lys158 and Lys164 sites. As an underlying molecular mechanism, we demonstrate that BAG3 interacts with GLS and decreases SIRT5 expression. The current study also demonstrates that occupation by succinyl at Lys158 and Lys164 sites prohibits its Lys48-linked ubiquitination, thereby preventing its subsequent proteasomal degradation. Collectively, the current study demonstrates that BAG3 enhances autophagy via stabilizing GLS and promoting glutaminolysis. For the first time, this study reports that succinylation competes with ubiquitination to regulate proteasomal GLS degradation.