Co-chaperone FKBP38 Promotes HERG Trafficking

The Long QT Syndrome is a cardiac disorder associated with ventricular arrhythmias that can lead to syncope and sudden death. One prominent form of the Long QT syndrome has been linked to mutations in the HERG gene (KCNH2) that encodes the voltage-dependent delayed rectifier potassium channel (IKr). In order to search for HERG-interacting proteins important for HERG maturation and trafficking, we conducted a proteomics screen using myc-tagged HERG transfected into cardiac (HL-1) and non-cardiac (human embryonic kidney 293) cell lines. A partial list of putative HERG-interacting proteins includes several known components of the cytosolic chaperone system, including Hsc70 (70-kDa heat shock cognate protein), Hsp90 (90-kDa heat shock protein), Hdj-2, Hop (Hsp-organizing protein), and Bag-2 (BCL-associated athanogene 2). In addition, two membrane-integrated proteins were identified, calnexin and FKBP38 (38-kDa FK506-binding protein, FKBP8). We show that FKBP38 immunoprecipitates and co-localizes with HERG in our cellular system. Importantly, small interfering RNA knock down of FKBP38 causes a reduction of HERG trafficking, and overexpression of FKBP38 is able to partially rescue the LQT2 trafficking mutant F805C. We propose that FKBP38 is a co-chaperone of HERG and contributes via the Hsc70/Hsp90 chaperone system to the trafficking of wild type and mutant HERG potassium channels. The Long QT Syndrome is a cardiac disorder associated with ventricular arrhythmias that can lead to syncope and sudden death. One prominent form of the Long QT syndrome has been linked to mutations in the HERG gene (KCNH2) that encodes the voltage-dependent delayed rectifier potassium channel (IKr). In order to search for HERG-interacting proteins important for HERG maturation and trafficking, we conducted a proteomics screen using myc-tagged HERG transfected into cardiac (HL-1) and non-cardiac (human embryonic kidney 293) cell lines. A partial list of putative HERG-interacting proteins includes several known components of the cytosolic chaperone system, including Hsc70 (70-kDa heat shock cognate protein), Hsp90 (90-kDa heat shock protein), Hdj-2, Hop (Hsp-organizing protein), and Bag-2 (BCL-associated athanogene 2). In addition, two membrane-integrated proteins were identified, calnexin and FKBP38 (38-kDa FK506-binding protein, FKBP8). We show that FKBP38 immunoprecipitates and co-localizes with HERG in our cellular system. Importantly, small interfering RNA knock down of FKBP38 causes a reduction of HERG trafficking, and overexpression of FKBP38 is able to partially rescue the LQT2 trafficking mutant F805C. We propose that FKBP38 is a co-chaperone of HERG and contributes via the Hsc70/Hsp90 chaperone system to the trafficking of wild type and mutant HERG potassium channels. The Long QT Syndrome is a cardiac disorder characterized by a prolongation of the QT interval on the surface electrocardiogram that has been associated with ventricular arrhythmias whose clinical features range from minor dizziness to seizure, syncope, and sudden death. One prominent form of the Long QT syndrome (LQT2) 2The abbreviations used are: LQTS, long QT syndrome; HERG, human ether-a-go-go-related gene; WT, wild type; ER, endoplasmic reticulum; Hsc70, 70-kDa heat shock cognate protein; Hsp90, 90-kDa heat shock protein; CFTR, cystic fibrosis transmembrane conductance regulator; CHIP, C-terminal of Hsp70-interacting protein; Bag-2, BCL-associated athanogene 2; Hop, Hsp-organizing protein; FKBP38, 38-kDa FK506-binding protein; TPR, tetratricopeptide repeat; HA, hemagglutinin; HERG-C, C terminus of HERG; HEK, human embryonic kidney; PBS, phosphate-buffered solution; siRNA, small interfering RNA; AU, arbitrary units. is localized to chromosome 7 (1Curran M.E. Splawski I. Timothy K.W. Vincent G.M. Green E.D. Keating M.T. Cell. 1995; 80: 795-803Abstract Full Text PDF PubMed Scopus (2002) Google Scholar) and has been linked to genetic mutations in the KCNH2 gene that encodes the HERG subunit. The HERG channel is a tetramer of HERG subunits that comprises the α-subunit of the voltage-dependent delayed rectifier potassium current (IKr) (2Sanguinetti M.C. Jiang C. Curran M.E. Keating M.T. Cell. 1995; 81: 299-307Abstract Full Text PDF PubMed Scopus (2161) Google Scholar). To date, more than 200 naturally occurring LQT2 mutants have been identified that result in either abnormal HERG channel function or a decrease in cell surface localization. Approximately 13% of these HERG mutations are characterized as trafficking-deficient mutants and represent the most dominant mechanism for the loss of HERG function in LQT2 (3Anderson C.L. Delisle B.P. Anson B.D. Kilby J.A. Will M.L. Tester D.J. Gong Q. Zhou Z. Ackerman M.J. January C.T. Circulation. 2006; 113: 365-373Crossref PubMed Scopus (337) Google Scholar). HERG trafficking mutants represent a potential target for pharmacological intervention as roughly 70% can be rescued, suggesting that the folding defects might be subtle (3Anderson C.L. Delisle B.P. Anson B.D. Kilby J.A. Will M.L. Tester D.J. Gong Q. Zhou Z. Ackerman M.J. January C.T. Circulation. 2006; 113: 365-373Crossref PubMed Scopus (337) Google Scholar). Under physiological conditions wild type (WT) HERG exhibits two bands on Western blot analysis, with the generation of both bands involving asparagine (Asn)-linked glycosylation (4Zhou Z. Gong Q. Ye B. Fan Z. Makielski J.C. Robertson G.A. January C.T. Biophys. J. 1998; 74: 230-241Abstract Full Text Full Text PDF PubMed Scopus (632) Google Scholar). The core-glycosylated, immature form is represented by a 135-kDa band and is present in the endoplasmic reticulum (ER), whereas the fully glycosylated mature protein is observable as a 155-kDa band and represents HERG either in the Golgi apparatus or at the cell surface (5Petrecca K. Atanasiu R. Akhavan A. Shrier A. J. Physiol. 1999; 515 (, Pt. 1,): 41-48Crossref PubMed Scopus (127) Google Scholar, 6Gong Q. Anderson C.L. January C.T. Zhou Z. Am. J. Physiol. 2002; 283 (-H84): H77Crossref PubMed Scopus (20) Google Scholar). Comparison of the intensity of these two bands provides a useful assay of HERG trafficking. The prevailing view is that mutants with trafficking deficiencies are recognized and retained as misfolded proteins by the quality control machinery of the ER (7Ellgaard L. Helenius A. Nat. Rev. Mol. Cell. Biol. 2003; 4: 181-191Crossref PubMed Scopus (1681) Google Scholar). Recently, it has been reported that HERG forms complexes with the molecular chaperones Hsc70 (70-kDa heat shock cognate protein), Hsp90 (90-kDa heat shock protein) (8Ficker E. Dennis A.T. Wang L. Brown A.M. Circ. Res. 2003; 92 (-e100): e87Crossref PubMed Google Scholar), and calnexin (9Gong Q. Jones M.A. Zhou Z. J. Biol. Chem. 2006; 281: 4069-4074Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar), which are known to be important for polypeptide folding, sorting, transport, and degradation (10McClellan A.J. Tam S. Kaganovich D. Frydman J. Nat. Cell Biol. 2005; 7: 736-741Crossref PubMed Scopus (228) Google Scholar, 11Young J.C. Agashe V.R. Siegers K. Hartl F.U. Nat. Rev. Mol. Cell Biol. 2004; 5: 781-791Crossref PubMed Scopus (944) Google Scholar). Ficker et al. (8Ficker E. Dennis A.T. Wang L. Brown A.M. Circ. Res. 2003; 92 (-e100): e87Crossref PubMed Google Scholar) demonstrated that two LQT2-trafficking mutants, R752W and G601S, also interacted with Hsc70 and Hsp90 when retained in the ER and these interactions were prolonged relative to WT HERG. The recovery of channel trafficking and function by temperature reduction or pharmacological stabilization was tightly coupled to the dissociation of channel-chaperone complexes (8Ficker E. Dennis A.T. Wang L. Brown A.M. Circ. Res. 2003; 92 (-e100): e87Crossref PubMed Google Scholar). This finding suggests that the Hsc70 and Hsp90 chaperone system is important for the folding of HERG and that regulation of exit from the ER is mechanistically linked to the dissociation of HERG from this complex. The Hsc70/Hsp90 network has been characterized more extensively for the cystic fibrosis transmembrane conductance regulator (CFTR) (12Wang X. Venable J. LaPointe P. Hutt D.M. Koulov A.V. Coppinger J. Gurkan C. Kellner W. Matteson J. Plutner H. Riordan J.R. Kelly J.W. Yates J.R. II I Balch W.E. Cell. 2006; 127: 803-815Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar, 13Riordan J.R. Annu. Rev. Physiol. 2005; 67: 701-718Crossref PubMed Scopus (193) Google Scholar) and the glucocorticoid receptor (14Hernandez M.P. Sullivan W.P. Toft D.O. J. Biol. Chem. 2002; 277: 38294-38304Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Thus far, interactions have been identified between CFTR and Hsc70 (15Yang Y. Janich S. Cohn J.A. Wilson J.M. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 9480-9484Crossref PubMed Scopus (282) Google Scholar), calnexin (16Pind S. Riordan J.R. Williams D.B. J. Biol. Chem. 1994; 269: 12784-12788Abstract Full Text PDF PubMed Google Scholar), Hsp90 (17Loo M.A. Jensen T.J. Cui L. Hou Y-X. Chang X.-B Riordan J.R. EMBO J. 1998; 17: 6879-6887Crossref PubMed Scopus (299) Google Scholar), Hdj-2 (18Meacham G.C. Lu Z. King S. Sorscher E. Tousson A. Cyr D.M. 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However, little is known about the protein complexes that form between HERG and molecular chaperones to facilitate HERG folding, maturation, and retention. To identify additional possible HERG-interacting chaperones we conducted a proteomic analysis. This revealed several known cytosolic chaperones, including Hsc70, Hsp90, Hdj-2, Hsp-organizing protein (Hop), and Bag-2 as well as two transmembrane proteins that included calnexin and FKBP38 (38-kDa FK506-binding protein, FKBP8). FKBP38 is of particular interest in that it is almost entirely exposed to the cytosol and is related to the known tetratricopeptide repeat (TPR) domain co-chaperone FKBP52 (23Peattie D.A. Harding M.W. Fleming M.A. DeCenzo M.T. Lippke J.A. Livingston D.J. Benasutti M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 10974-10978Crossref PubMed Scopus (231) Google Scholar). of a domain to with Hsc70 Hsp90, a and a C-terminal transmembrane E. M. 1995; PubMed Scopus Google Scholar). The domain of FKBP38 is related to the domain present in of Hsc70 and co-chaperone as in Hop, between Hsc70 and as that in CHIP, can either Hsc70 or Hsp90 J.C. Agashe V.R. Siegers K. Hartl F.U. Nat. Rev. Mol. Cell Biol. 2004; 5: 781-791Crossref PubMed Scopus (944) Google Scholar). The of Hsc70 and Hsp90 by is known C. A. S. L. H. Hartl F.U. I. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), and the are in We that as a protein FKBP38 a between the cytosolic chaperones and ER or of HERG. we the and of FKBP38 on WT HERG and a HERG trafficking that FKBP38 is important for the trafficking of WT HERG and is of the LQT2 HERG trafficking mutant F805C. of generation of and HERG has been A. Atanasiu R. Shrier A. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The HERG mutant was using the and a as the as A. Atanasiu R. Shrier A. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The of FKBP38 was by M. Nat. Cell Biol. 2003; 5: PubMed Scopus Google Scholar). Cell and and were used and as A. Atanasiu R. Shrier A. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). were in with and were at in were using either or as by the were used Cell cell for WT HERG was using the transfected were in with of for to were by protein and as by Western blot and and proteomic of HERG transfected into cardiac (HL-1) D.B. A. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, Am. J. Physiol. 2004; PubMed Scopus Google Scholar) and non-cardiac cell were The complexes were by and by bands were and with using a at the of the The were by The were using to identify to the for protein and with a of or D.M. 1999; PubMed Scopus Google Scholar). were from the as M. M. Chem. 1994; PubMed Scopus Google Scholar). The and function of identified protein were using and and Western were two with and in and a for a of were by and on for additional with was at for which the was and the protein was with a assay to the of to of protein were in a of to and at with either or by The were with for 2 which the were extensively and in were on a and to The were for with and in and with the for at and with to the were on using the and overexpression on were transfected at with WT or HERG and of or and of to of transfected were as and of protein were and to and Western blot analysis. the in the of human FKBP38 and a control RNA with a were from on M. Nat. Cell Biol. 2003; 5: PubMed Scopus Google were at on and transfected with to the using and were or and to and Western blot as WT were were with and for with at temperature on were with and with in for was by for at temperature which were with either or for were extensively with either or at with the were using were with a 200 and was using the of band was by a of for the and HERG bands and the FKBP38 band were to the control protein both the and overexpression HERG trafficking is represented by the of the HERG band to the HERG intensity HERG were in were used to of to HERG with search for possible chaperones or that with HERG we conducted a of proteomic of HERG transfected into cardiac (HL-1) D.B. A. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, Am. J. Physiol. 2004; PubMed Scopus Google Scholar) and non-cardiac cell lines. The complexes were by to and by at the HERG-interacting chaperones and Hsc70, Hsp90, Hop, Bag-2, and calnexin In to these cytosolic chaperones we identified the FKBP38, a putative co-chaperone that with the Hsc70/Hsp90 chaperone network in the HERG HERG-interacting chaperones and protein was in conducted in protein was in conducted in heat shock cognate heat shock Hsp-organizing athanogene FK506-binding protein, TPR, I protein protein was in conducted in protein was in conducted in in a HERG and FKBP38 and FKBP38 is it is in in the and the E. M. 1995; PubMed Scopus Google Scholar). To that is between HERG and FKBP38 we conducted were transfected with WT HERG and and with in both the mature and immature forms of HERG were with the FKBP38 with both forms of the HERG protein, that most chaperones it has that FKBP38 is to HERG from the This might be FKBP38 is in a HERG folding or in the ER exit of HERG. we transfected with WT HERG, or WT HERG and and with either or the of a band at that to FKBP38, that FKBP38 is with both and WT HERG with the were conducted in or WT HERG and in the that HERG can FKBP38 whereas the these that HERG and FKBP38 and that the two proteins are present in the cellular FKBP38 to the of the C-terminal it is to a in the regulation of with M. Nat. Cell Biol. 2003; 5: PubMed Scopus Google Scholar). and cell that FKBP38 at both the ER and M. Nat. Cell Biol. 2003; 5: PubMed Scopus Google Scholar, M. J. EMBO J. 2005; PubMed Scopus Google Scholar, J. J. 2005; PubMed Scopus Google Scholar). To the ER of FKBP38 in our system we in and in 2 is between the ER and FKBP38 that FKBP38 is localized to the ER as well as the To HERG and FKBP38 in our cell system we HERG with and the between the two proteins that in To these two proteins also in a more physiological system, we transfected HERG into a cardiac cell (HL-1) and with for HERG and for that to was in the when the were transfected with HERG is of HERG and FKBP38 that as a these show that FKBP38 is in the ER it co-localizes with co-localizes with FKBP38 in a cardiac (HL-1) and a non-cardiac cell were in HERG. HERG and FKBP38 were using a and by transfected with HERG were as for that was used of for HERG A and the represents a to the of the FKBP38 HERG the between HERG and FKBP38 has a in the trafficking of HERG we used to the of FKBP38 in the cell Under control both the glycosylated ER form and the mature glycosylated form of HERG were by Western blot at and The reduction of FKBP38 a of FKBP38 by 2 whereas a on the of FKBP38 Importantly, this FKBP38 knock down on 2 to a reduction in the HERG trafficking relative to control on relative to control arbitrary and relative to control We the in the FKBP38 reduction of HERG trafficking to the relative of FKBP38 and HERG. HERG is a protein with a of at the cell a of mature HERG be on 2 when FKBP38 are at the on as the reduction of FKBP38 in a decrease in the of HERG FKBP38 of that knock down of FKBP38 HERG maturation, we overexpression of FKBP38 HERG maturation rescue a HERG trafficking To these we FKBP38 in the of either WT HERG or the HERG trafficking mutant F805C. The is present in the domain B.P. Anderson C.L. Anson B.D. T.J. January C.T. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) and can be by a reduction in temperature E. S. Brown A.M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) or by the reticulum B.P. Anderson C.L. Anson B.D. T.J. January C.T. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). in FKBP38 or of or were transfected with WT HERG or into and the HERG was by Western WT HERG, of FKBP38 overexpression on trafficking of and for WT with or of FKBP38, However, as in and in overexpression of FKBP38 at both and of was able to partially rescue the trafficking of the mutant of and for with or of FKBP38, which is retained in the ER and on Western blot as a when as protein was the trafficking is between WT and at of FKBP38 we that the rescue is of is for WT HERG. This result that a of these have the The of this is that FKBP38 with the HERG potassium channel and trafficking This on trafficking is in two overexpression of FKBP38 partially the LQT2 trafficking mutant F805C. In addition, when FKBP38 protein are by siRNA, is a reduction in WT HERG trafficking We that HERG and FKBP38 in the ER HERG and that this is for exit of HERG from the We propose a in which FKBP38 to present HERG to the ER The that FKBP38 is in the of the folding of HERG and be in ER is by the that the of FKBP38 with the immature ER form of HERG and is a minor with the fully glycosylated form of HERG. The that a small of fully glycosylated HERG with FKBP38 suggests that the two proteins are as HERG is to the Golgi glycosylation FKBP38 the by which HERG it that it from HERG. To this that the between FKBP38 and HERG be to the To date, most of FKBP38 in the regulation of with M. Nat. Cell Biol. 2003; 5: PubMed Scopus Google Scholar, M. J. EMBO J. 2005; PubMed Scopus Google Scholar, J. J. 2005; PubMed Scopus Google Scholar, L. J. Biophys. Res. 2005; PubMed Scopus Google Scholar, M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, it has been that can as chaperones by C. C. 2001; PubMed Scopus Google Scholar). we are a for FKBP38 as a co-chaperone of the Hsc70/Hsp90 chaperone system of HERG. A has been by Wang et al. (12Wang X. Venable J. LaPointe P. Hutt D.M. Koulov A.V. Coppinger J. Gurkan C. Kellner W. Matteson J. Plutner H. Riordan J.R. Kelly J.W. Yates J.R. II I Balch W.E. Cell. 2006; 127: 803-815Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar) in the folding of This used proteomics to identify to as the This of proteins of several of the Hsc70/Hsp90 chaperone network that in interactions with and WT CFTR, including the co-chaperone are between the of FKBP38 on the trafficking of and our on the trafficking of Wang et al. (12Wang X. Venable J. LaPointe P. Hutt D.M. Koulov A.V. Coppinger J. Gurkan C. Kellner W. Matteson J. Plutner H. Riordan J.R. Kelly J.W. Yates J.R. II I Balch W.E. Cell. 2006; 127: 803-815Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar) that knock down of FKBP38 in a reduction in both the ER and Golgi bands of This is to the that knock down on WT HERG trafficking. that overexpression of FKBP38 also a reduction in both ER and Golgi bands of to that FKBP38 function and are to the of Hsp90 and of the folding that FKBP38 the of in the ER whereas we show that it HERG trafficking To the in the of FKBP38 overexpression on CFTR HERG we that the of for folding and are and cell that the have on proteins HERG and The co-chaperone for FKBP38 is in by of a which a in receptor Toft D.O. Biol. 2003; PubMed Scopus Google Scholar). In the of the Hsc70 and Hsp90 with several including FKBP52 to a in the of the receptor Y. 2004; PubMed Scopus Google Scholar). in the of are in by both Hsc70 and Hdj-2, at which The receptor that it can Hsp90 and the is Hsp90 Hop from the Hsp90, and to Hsp90 (14Hernandez M.P. Sullivan W.P. Toft D.O. J. Biol. Chem. 2002; 277: 38294-38304Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). The dissociation of Hop from the receptor a domain on Hsp90 to the domain of the is that FKBP52 is for the trafficking of to the by to to for the into the A.M. Cell. 1999; PubMed Scopus Google Scholar, A.M. C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, C. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J.M. M. C. J.M. Zhang M. 2002; PubMed Scopus Google Scholar). that of the chaperones and for FKBP52 were with HERG, we that FKBP38 as Hsp90 co-chaperone in the WT HERG maturation we that WT HERG is from chaperone in a and the ER, in a with interactions and at are of the chaperones or to the FKBP38 a in the of HERG to the protein as FKBP52 with the and for to the via with the domain of FKBP38 and the domain at the C terminus of the A. R. B. W. J. Res. Cell 2006; PubMed Scopus Google Scholar, M.J. EMBO J. 2006; PubMed Scopus Google Scholar, 1998; PubMed Scopus Google Scholar). are to this In to WT HERG, a that with the chaperone of Hdj-2, Hsc70, Hop, and Hsp90 is prolonged (8Ficker E. Dennis A.T. Wang L. Brown A.M. Circ. Res. 2003; 92 (-e100): e87Crossref PubMed Google Scholar, Q. Jones M.A. Zhou Z. J. Biol. Chem. 2006; 281: 4069-4074Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). The mutant is recognized by these chaperones as and additional are to the these to the protein it is that Hop on Hsc70, which the mutant protein for degradation as is known to with the CFTR mutant (20Meacham G.C. Patterson C. Zhang W. Younger J.M. Cyr D.M. Nat. Cell Biol. 2001; 3: 100-105Crossref PubMed Scopus (707) Google Scholar, 21Younger J.M. Ren H-Y. Chen L. Fan C.-Y. Fields A. Patterson C. Cyr D.M. J. Cell Biol. 2004; 167: 1075-1085Crossref PubMed Scopus (145) Google Scholar). has demonstrated for the that FKBP38 with Hsp90 domain and that FKBP38 is by Hsp90 M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). One is that FKBP38 and Hsp90 function in with to the trafficking of HERG mutants and that the of FKBP38 with HERG and Hsp90 the of the The that FKBP38 overexpression the trafficking of suggests that it be a co-chaperone in this interest is the that FKBP38 overexpression the trafficking of it on the trafficking of WT HERG. in the that rescue of a trafficking mutant with of WT trafficking. Ficker et al. E. S. Brown A.M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) that and the trafficking of the HERG trafficking mutant G601S, of the on the trafficking of WT HERG. the that that is of HERG trafficking mutants, it is that HERG has ER exit The current provides of a HERG trafficking mutant that can be by overexpression of is entirely possible that a of is to rescue HERG trafficking We K. I. for the FKBP38 and the to FKBP38, Y. Q. for and J. C. for and of

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