The TWK-26/KCNK3 potassium channel and FLR-4 protein kinase coordinate nutrient absorption in the C. elegans intestine

Ion channels are necessary for proper water and nutrient absorption in the intestine, thereby supporting cellular metabolism and organismal growth. While a role for Na+ co-transporters and pumps in intestinal nutrient absorption is well defined, how individual K+ uniporters function in this process is poorly understood. Mutations in the Caenorhabditis elegans genes drl-1 and flr-4, which encode two unique kinases that are components of a mitogen-activated protein kinase (MAPK) pathway, or the flr-1 Na+ ion channel, cause severe growth defects, reduced lipid storage, and a dramatic increase in autophagic lysosomes. Here, we show that a gain-of-function mutation in twk-26, which encodes a 2-pore domain K+ ion channel orthologous to human KCNK3, facilitates nutrient absorption and suppresses the metabolic and developmental defects caused by loss of DRL-1, FLR-4, or FLR-1 signaling. We reveal that these phenotypes likely arise from impaired intestinal amino acid absorption, which is restored upon activation of TWK-26. Furthermore, we show that loss of flr-4 disrupts intracellular and extracellular pH gradients, suggesting that the FLR-4 pathway may be necessary to maintain intestinal ion homeostasis and facilitate nutrient absorption. Importantly, the altered pH gradients in the flr-4 mutant are partially restored by the twk-26 gain-of-function mutation. Thus, this study uncovers a new role for the TWK-26 ion channel in governing intestinal physiology and metabolism.