Journal
JOURNAL OF CELL SCIENCE
Volume 125, Issue 19, Pages 4662-4675Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.110296
Keywords
Myristoyl switch; Protein trafficking; Ubiquitylation; Na+/K(+)ATPase; Na+ pump
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Funding
- UK Medical Research Council [MC_U127084354]
- AstraZeneca
- Boehringer Ingelheim
- GlaxoSmithKline
- Merck-Serono
- Pfizer
- MRC [MC_EX_G0801767, G1100713, MC_U127084354] Funding Source: UKRI
- Medical Research Council [G1100713, MC_EX_G0801767, MC_U127084354] Funding Source: researchfish
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Here, we describe a phosphorylation-based reverse myristoyl switch for mammalian ZNRF2, and show that this E3 ubiquitin ligase and its sister protein ZNRF1 regulate the Na+/K+ pump (Na+/K(+)ATPase). N-myristoylation localizes ZNRF1 and ZNRF2 to intracellular membranes and enhances their activity. However, when ZNRF2 is phosphorylated in response to agonists including insulin and growth factors, it binds to 14-3-3 and is released into the cytosol. On membranes, ZNRF1 and ZNRF2 interact with the Na+/K(+)ATPase alpha 1 subunit via their UBZ domains, while their RING domains interact with E2 proteins, predominantly Ubc13 that, together with Uev1a, mediates formation of Lys63-ubiquitin linkages. ZNRF1 and ZNRF2 can ubiquitylate the cytoplasmic loop encompassing the nucleotide-binding and phosphorylation regions of the Na+/K(+)ATPase alpha 1 subunit. Ouabain, a Na+/K(+)ATPase inhibitor and therapeutic cardiac glycoside, decreases ZNRF1 protein levels, whereas knockdown of ZNRF2 inhibits the ouabain-induced decrease of cell surface and total Na+/K(+)ATPase alpha 1 levels. Thus, ZNRF1 and ZNRF2 are new players in regulation of the ubiquitous Na+/K(+)ATPase that is tuned to changing demands in many physiological contexts.
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