Abstract
Mutations in the skeletal muscle-specific CLC-1 chloride channel are associated with the human hereditary disease myotonia congenita. The molecular pathophysiology underlying some of the disease-causing mutations can be ascribed to defective human CLC-1 protein biosynthesis. CLC-1 protein folding is assisted by several molecular chaperones and co-chaperones, including FK506-binding protein 8 (FKBP8). FKBP8 is generally considered an endoplasmic reticulum- and mitochondrion-resident membrane protein, but is not thought to contribute to protein quality control at the cell surface. Herein, we aim to test the hypothesis that FKBP8 may regulate CLC-1 protein at the plasma membrane. Surface biotinylation and subcellular fractionation analyses reveal that a portion of FKBP8 is present at the plasma membrane, and that co-expression with CLC-1 enhances surface localization of FKBP8. Immunoblotting analyses of plasma membrane proteins purified from skeletal muscle further confirm surface localization of FKBP8. Importantly, FKBP8 promotes CLC-1 protein stability at the plasma membrane. Together, our data underscore the importance of FKBP8 in the peripheral quality control of CLC-1 channel.
Highlights
In skeletal muscles, up to 80% of the resting membrane conductance is determined by the voltage-dependent CLC-1 chloride (Cl−) channel [1,2,3], indicating that the Cl− channel is essential for setting the resting membrane potential after firing of action potentials
Based on the mean F(3+4)/F8 ratios derived from our sucrose density gradient analyses, FK506-binding protein 8 (FKBP8) (~0.12–0.34) does display a markedly reduced propensity for cell surface localization, as compared to typical plasma membrane proteins such as cadherin (~6.31–9.02), CLC-1 (~1.87–2.92), and KV1.1 (~0.66–1.23)
We previously demonstrated that the molecular chaperones Hsc70 and Hsp90β, as well as the co-chaperones HOP, Aha1, and FKBP8, are binding partners of human CLC-1 channel [19]
Summary
Up to 80% of the resting membrane conductance is determined by the voltage-dependent CLC-1 chloride (Cl−) channel [1,2,3], indicating that the Cl− channel is essential for setting the resting membrane potential after firing of action potentials. Tthheeaastbesriesnkce or presednecneootefsFalasgig-nCiLfiCca-n1t cdoif-feexrpenrceessfiroonm; t(hDe)cSotnattrioslti(c*,atl-taensta:lpys
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