Zhou R, Tomkovicz VR, Butler PL, Ochoa LA, Peterson ZJ, Snyder PM

Ubiquitination plays a key role in trafficking of the epithelial Na(+) channel ENaC. Previous work indicates that ubiquitination enhances ENaC endocytosis and sorting to lysosomes for degradation. Moreover, a defect in ubiquitination causes Liddle's syndrome, an inherited form of hypertension. In the current work, we identified a role for ubiquitin ...

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specific peptidase 8 (USP8) in the control of ENaC ubiquitination and trafficking. USP8 increased ENaC current in Xenopus oocytes and collecting duct epithelia, and enhanced ENaC abundance at the cell surface in HEK 293 cells. This resulted from altered endocytic sorting; USP8 abolished ENaC degradation in the endocytic pathway, but it had no effect on ENaC endocytosis. USP8 interacted with ENaC, as detected by coimmunoprecipitation, and it deubiquitinated ENaC. Consistent with a functional role for deubiquitination, mutation of ENaC's cytoplasmic lysines reduced the effect of USP8 on ENaC cell surface abundance. In contrast to USP8, ubiquitin specific peptidase 2-45 increased ENaC surface abundance by reducing endocytosis but not degradation. Thus, USP8 and USP2-45 selectively modulate ENaC trafficking at different steps in the endocytic pathway. Together with previous work, the data indicate that the ubiquitination state of ENaC is critical for the regulation of epithelial Na(+) absorption.

Date: Jan. 07, 2013

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