STAT3 associates with vacuolar H^＋-ATPase and regulates cytosolic and lysosomal pH  

作　　者：Bin Liu Johan Palmfeldt Lin Lin Alexandria Colaco Knut K. B, Clemmensen Jinrong Huang Fengping Xu Xin Liu Kenji Maeda Yonglun Luo Marja Jaattela 

机构地区：[1]Cell Death and Metabolism, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center (DCRC), DK-2100 Copenhagen, Denmark [2]Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital and Faculty of Health, Aarhus University, DK-8200 Aarhus, Denmark [3]Department of Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark [4]BGI-Shenzhen, Shenzhen, Guangdong 518083, China [5]Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark [6]BGI-Qingdao, Qingdao, Shandong 266555, China [7]Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark

出　　处：《Cell Research》2018年第10期996-1012,共17页细胞研究（英文版）

摘　　要：Dysregulated intracellular pH is emerging as a hallmark of cancer. In spite of their acidic environment and increased acid production, cancer cells maintain alkaline intracellular pH that promotes cancer progression by inhibiting apoptosis and increasing glycolysis, cell growth, migration, and invasion. Here we identify signa transducer and activator of transcription-3 （STAT3） as a key factor in the preservation of alkaline cytosol. STAT3 associates with the vacuolar H^＋-ATPase in a coiled-coil domain-dependent manner and increases its activity in living cells and in vitro. Accordingly, STAT3 depletion disrupts intracellular proton equilibrium by decreasing cytosolic pH and increasing lysosomal pH, respectively. This dysregulation can be reverted by reconstitution with wild-type STAT3 or STAT3 mutants unable to activate target genes （Tyr7OSPhe and DNA-binding mutant） or to regulate mitochondrial respiration （Ser727Ala）. Upon cytosolic acidification, STAT3 is transcriptionally inactivated and further recruited to lysosomal membranes to reestablish intracellular proton equ ilibrium. These data reveal STAT3 as a regulator of intracellular pH and, vice versa, intracellular pH as a regulator of STAT3 localization and activity.

关 键 词：STAT3 PH 调整 apoptosis 质子平衡 细胞内 细胞生长 目标基因 

分 类 号：Q756[生物学—分子生物学] X703[环境科学与工程—环境工程]