TMEM175 Is an Organelle K+ Channel Regulating Lysosomal Function

Summary Potassium is the most abundant ion to face both plasma and organelle membranes. Extensive research over the past seven decades has characterized how K + permeates the plasma membrane to control fundamental processes such as secretion, neuronal communication, and heartbeat. However, how K + permeates organelles such as lysosomes and endosomes is unknown. Here, we directly recorded organelle K + conductance and discovered a major K + -selective channel K EL on endosomes and lysosomes. K EL is formed by TMEM175, a protein with unknown function. Unlike any of the ∼80 plasma membrane K + channels, TMEM175 has two repeats of 6-transmembrane-spanning segments and has no GYG K + channel sequence signature-containing, pore-forming P loop. Lysosomes lacking TMEM175 exhibit no K + conductance, have a markedly depolarized ΔΨ and little sensitivity to changes in [K + ], and have compromised luminal pH stability and abnormal fusion with autophagosomes during autophagy. Thus, TMEM175 comprises a K + channel that underlies the molecular mechanism of lysosomal K + permeability.