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BAG3 promotes autophagy and glutaminolysis via stabilizing glutaminase.

Cell death & disease (2019-03-27)
Song Zhao, Jia-Mei Wang, Jing Yan, Da-Lin Zhang, Bao-Qin Liu, Jing-Yi Jiang, Chao Li, Si Li, Xiao-Na Meng, Hua-Qin Wang
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Glutamate Assay Kit, sufficient for 100 colorimetric tests
Sigma-Aldrich
Monoclonal Anti-GLS antibody produced in mouse, clone 5C4, purified immunoglobulin, buffered aqueous solution
Sigma-Aldrich
Anti-GAPDH Antibody, from chicken, purified by affinity chromatography
Sigma-Aldrich
Ammonia Assay Kit, sufficient for 100 assays