5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      FKBP8 Enhances Protein Stability of the CLC-1 Chloride Channel at the Plasma Membrane

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references53

          • Record: found
          • Abstract: found
          • Article: not found

          Rapid redistribution of Golgi proteins into the ER in cells treated with brefeldin A: Evidence for membrane cycling from Golgi to ER

          In cells treated with brefeldin A (BFA), movement of newly synthesized membrane proteins from the endoplasmic reticulum (ER) to the Golgi apparatus was blocked. Surprisingly, the glycoproteins retained in the ER were rapidly processed by cis/medial Golgi enzymes but not by trans Golgi enzymes. An explanation for these observations was provided from morphological studies at both the light and electron microscopic levels using markers for the cis/medial and trans Golgi. They revealed a rapid and dramatic redistribution to the ER of components of the cis/medial but not the trans Golgi in response to treatment with BFA. Upon removal of BFA, the morphology of the Golgi apparatus was rapidly reestablished and proteins normally transported out of the ER were efficiently and rapidly sorted to their final destinations. These results suggest that BFA disrupts a dynamic membrane-recycling pathway between the ER and cis/medial Golgi, effectively blocking membrane transport out of but not back to the ER.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Characterization of a cis-Golgi matrix protein, GM130

            Antisera raised to a detergent- and salt-resistant matrix fraction from rat liver Golgi stacks were used to screen an expression library from rat liver cDNA. A full-length clone was obtained encoding a protein of 130 kD (termed GM130), the COOH-terminal domain of which was highly homologous to a Golgi human auto-antigen, golgin-95 (Fritzler et al., 1993). Biochemical data showed that GM130 is a peripheral cytoplasmic protein that is tightly bound to Golgi membranes and part of a larger oligomeric complex. Predictions from the protein sequence suggest that GM130 is an extended rod-like protein with coiled-coil domains. Immunofluorescence microscopy showed partial overlap with medial- and trans-Golgi markers but almost complete overlap with the cis-Golgi network (CGN) marker, syntaxin5. Immunoelectron microscopy confirmed this location showing that most of the GM130 was located in the CGN and in one or two cisternae on the cis-side of the Golgi stack. GM130 was not re-distributed to the ER in the presence of brefeldin A but maintained its overlap with syntaxin5 and a partial overlap with the ER- Golgi intermediate compartment marker, p53. Together these results suggest that GM130 is part of a cis-Golgi matrix and has a role in maintaining cis-Golgi structure.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.

              The pathways that distinguish transport of folded and misfolded cargo through the exocytic (secretory) pathway of eukaryotic cells remain unknown. Using proteomics to assess global cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein interactions (the CFTR interactome), we show that Hsp90 cochaperones modulate Hsp90-dependent stability of CFTR protein folding in the endoplasmic reticulum (ER). Cell-surface rescue of the most common disease variant that is restricted to the ER, DeltaF508, can be initiated by partial siRNA silencing of the Hsp90 cochaperone ATPase regulator Aha1. We propose that failure of DeltaF508 to achieve an energetically favorable fold in response to the steady-state dynamics of the chaperone folding environment (the "chaperome") is responsible for the pathophysiology of CF. The activity of cargo-associated chaperome components may be a common mechanism regulating folding for ER exit, providing a general framework for correction of misfolding disease.
                Bookmark

                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                28 November 2018
                December 2018
                : 19
                : 12
                : 3783
                Affiliations
                [1 ]Department of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan; yijhengp@ 123456usc.edu (Y.-J.P.); angela2747@ 123456yahoo.com.tw (Y.-C.L.); d01441001@ 123456ntu.edu.tw (S.-J.F.); wingtalk1006@ 123456hotmail.com (Y.-C.C.)
                [2 ]Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 10051, Taiwan; cassis0211@ 123456hotmail.com
                [3 ]Neuroscience Center, University of California, Davis, CA 95616, USA; tycchen@ 123456ucdavis.edu
                [4 ]Brain Research Center, National Yang-Ming University, Taipei 12212, Taiwan
                [5 ]Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
                Author notes
                [* ]Correspondence: cjjeng@ 123456ym.edu.tw (C.-J.J.); tang@ 123456ntu.edu.tw (C.-Y.T.); Tel.: +886-2-2826-7072 (C.-J.J.); +886-2-2356-2215 (C.-Y.T.); Fax: +886-2-2821-2884 (C.-J.J.); +886-2-2396-4350 (C.-Y.T.)
                Author information
                https://orcid.org/0000-0001-6271-5704
                https://orcid.org/0000-0003-1065-2865
                Article
                ijms-19-03783
                10.3390/ijms19123783
                6320802
                30487393
                e31c5570-83bf-403a-b99d-1e2c417b04af
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 26 October 2018
                : 26 November 2018
                Categories
                Article

                Molecular biology
                ion channels,molecular chaperones,membrane proteins,protein stability,trafficking,skeletal muscle

                Comments

                Comment on this article