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The metabolic sensor AMP-activated protein kinase (AMPK) inhibits the epithelial Na +  channel (ENaC), a key regulator of salt reabsorption by the kidney and thus total body volume and blood pressure. Recent studies have suggested that AMPK promotes the association of p21-activated kinase-interacting exchange factor-β 1  β 1 Pix, 14-3-3 proteins, and the ubiquitin ligase neural precursor cell expressed developmentally downregulated protein (Nedd)4-2 into a complex that inhibits ENaC by enhancing Nedd4-2 binding to ENaC and ENaC degradation. Functional β 1 Pix is required for ENaC inhibition by AMPK and promotes Nedd4-2 phosphorylation and stability in mouse kidney cortical collecting duct cells. Here, we report that AMPK directly phosphorylates β 1 Pix in vitro. Among several AMPK phosphorylation sites on β 1 Pix detected by mass spectrometry, Ser 71  was validated as functionally significant. Compared with wild-type β 1 Pix, overexpression of a phosphorylation-deficient β 1 Pix-S71A mutant attenuated ENaC inhibition and the AMPK-activated interaction of both β 1 Pix and Nedd4-2 to 14-3-3 proteins in cortical collecting duct cells. Similarly, overexpression of a β 1 Pix-Δ602–611 deletion tract mutant unable to bind 14-3-3 proteins decreased the interaction between Nedd4-2 and 14-3-3 proteins, suggesting that 14-3-3 binding to β 1 Pix is critical for the formation of a β 1 Pix/Nedd4-2/14-3-3 complex. With expression of a general peptide inhibitor of 14-3-3-target protein interactions (R18), binding of both β 1 Pix and Nedd4-2 to 14-3-3 proteins was reduced, and AMPK-dependent ENaC inhibition was also attenuated. Altogether, our results demonstrate the importance of AMPK-mediated phosphorylation of β 1 Pix at Ser 71 , which promotes 14-3-3 interactions with β 1 Pix and Nedd4-2 to form a tripartite ENaC inhibitory complex, in the mechanism of ENaC regulation by AMPK.

american journal of physiology. renal physiology./american journal of physiology. renal physiology

AMPK phosphorylation of the β<sub>1</sub>Pix exchange factor regulates the assembly and function of an ENaC inhibitory complex in kidney epithelial cells

AMPK phosphorylation of the β1Pix exchange factor regulates the assembly and function of an ENaC inhibitory complex in kidney epithelial cells

AMPK phosphorylation of the β₁Pix exchange factor regulates the assembly and function of an ENaC inhibitory complex in kidney epithelial cells