The inhibitory SAPS3 – AMPK interaction detected in HEK293 cells is not detectable in muscle or liver from humans or mice

It has been proposed that the regulatory Sit4-associated protein subunit 3 (SAPS3) of protein phosphatase 6 (PP6C) acts as an AMP-activated protein kinase (AMPK) inhibitor by recruiting PP6C to dephosphorylate AMPKα-T172. While we confirm this interaction in HEK293 cells, we find limited evidence for a SAPS3–AMPK interaction in metabolically perturbed liver and skeletal muscle from humans and mice. Across fasting, high-fat diet feeding, and exercise conditions, co-immunoprecipitation assays failed to detect endogenous SAPS3–AMPK and PP6C–AMPK interactions. These findings challenge the physiological relevance of SAPS3/PP6C as regulators of AMPK in mature tissues and highlight the need for further investigation into the regulation of AMPK by protein phosphatases in vivo.

有研究提出，蛋白磷酸酶6（PP6C）的调节性Sit4相关蛋白亚基3（SAPS3）可通过招募PP6C对腺苷酸活化蛋白激酶（AMPK）α亚基T172位点进行去磷酸化，从而发挥AMPK抑制剂的作用。本研究在HEK293细胞中证实了二者的相互作用，但在代谢扰动的人类及小鼠肝脏与骨骼肌组织中，仅能获取到极有限的SAPS3与AMPK相互作用相关证据。在禁食、高脂饮食喂养及运动这三种代谢应激条件下，免疫共沉淀实验均未能检测到内源性的SAPS3-AMPK与PP6C-AMPK相互作用。上述研究结果对"SAPS3/PP6C作为成熟组织中AMPK的调控因子"这一观点的生理相关性提出了挑战，并凸显了在体内层面进一步探究蛋白磷酸酶对AMPK调控机制的必要性。