Description
Lysosomal STAT3 Regulates Intracellular Proton Equilibrium
Bin Liu1, Johan Palmfeldt2, Yonglun Luo3, Lin Lin3, Alexandria Colaço1, Kenji Maeda1, Marja Jäättelä1
1Cell Death and Metabolism, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center (DCRC), Copenhagen, Denmark, 2Department of Clinical Medicine, Aarhus University Hospital and Faculty of Health, Aarhus University, Aarhus, Denmark, 3Department of Biomedicine, Aarhus University, Aarhus, Denmark
Dysregulated intracellular pH is emerging as a hallmark of cancer. In spite of their acidic environment, cancer cells maintain alkaline intracellular pH (≥7.4) that promotes cancer progression by inhibiting apoptosis and increasing glycolysis, cell growth, migration and invasion. Here, we identify signal transducer and activator of transcription 3 (STAT3) as a key player in the maintenance of alkaline cytosolic pH. STAT3 associates with the vacuolar H+-ATPase on lysosomal membranes 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 and increasing cytosolic and lysosomal pH, respectively. This dysregulation can be reverted by reconstitution with wild type STAT3 as well as STAT3 mutants unable to activate target genes (Tyr-705-Phe and DNA binding mutant) or to regulate mitochondrial respiration (Ser-727-Ala). Upon cytosolic acidification, phospho-Tyr-705-STAT3 is rapidly dephosphorylated, transcriptionally inactivated and further recruited to lysosomal membranes to reestablish intracellular proton equilibrium and to enhance cell survival. These data reveal STAT3 as a regulator of intracellular pH, and vice versa intracellular pH as a regulator of STAT3 localization and activity.
Financial Support: Grants from the European Research Council (ERC AdG 340751), Danish Cancer Society (R124-A7929; R90-A5783), Danish National Research Foundation (DNRF125), Danish Council for Independent Research (4092-00157B, DFF-1337-00128, DFF-1335-0076A and 6108-00542), John and Birthe Meyer Foundation, and Novo Nordisk Foundation (NNF15OC0016914).