CHIF a member of the FXYD protein family is a regulator of NaK-ATPase distinct from the γ-subunit

摘要

The biological role of small membrane proteins of the new FXYD family is largely unknown. The best characterized FXYD protein is the γ-subunit of the Na,K-ATPase (NKA) that modulates the Na,K-pump function in the kidney. Here, we report that, similarly to γa and γb splice variants, the FXYD protein CHIF (corticosteroid-induced factor) is a type I membrane protein which is associated with NKA in renal tissue, and modulates the Na,K-pump transport when expressed in Xenopus oocytes. In contrast to γa and γb, which both decrease the apparent Na⁺ affinity of the Na,K-pump, CHIF significantly increases the Na⁺ affinity and decreases the apparent K⁺ affinity due to an increased Na⁺ competition at external binding sites. The extracytoplasmic FXYD motif is required for stable γ-subunit and CHIF interaction with NKA, while cytoplasmic, positively charged residues are necessary for the γ-subunit’s association efficiency and for CHIF’s functional effects. These data document that CHIF is a new tissue-specific regulator of NKA which probably plays a crucial role in aldosterone-responsive tissues responsible for the maintenance of body Na⁺ and K⁺ homeostasis.