The PDZ-binding Chloride Channel ClC-3B Localizes to the Golgi and Associates with Cystic Fibrosis Transmembrane Conductance Regulator-interacting PDZ Proteins

Abstract

. ClC-3A resides in late endosomes where it serves as an anion shunt during acidification. We show here that the ClC-3B PDZ-binding isoform resides in the Golgi where it co-localizes with a small amount of the other known PDZ-binding chloride channel, CFTR (cystic fibrosis transmembrane conductance regulator). Both channel proteins bind the Golgi PDZ protein, GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein). Interestingly, however, when overexpressed, GOPC, which is thought to influence traffic in the endocytic/secretory pathway, causes a large reduction in the amounts of both channels, probably by leading them to the degradative end of this pathway. ClC-3B as well as CFTR also binds EBP50 (ERM-binding phosphoprotein 50) and PDZK1, which are concentrated at the plasma membrane. However, only PDZK1 was found to promote interaction between the two channels, perhaps because they were able to bind to two different PDZ domains in PDZK1. Thus while small portions of the populations of ClC-3B and CFTR may associate and co-localize, the bulk of the two populations reside in different organelles of cells where they are expressed heterologously or endogenously, and therefore their cellular functions are likely to be distinct and not primarily related.

Evidence for a Functional Interaction between the ClC-2 Chloride Channel and the Retrograde Motor Dynein Complex

“…Two other members of this family, ClC-3 and ClC-5, have been localized to endosomal compartments (39 -41). However, unlike ClC-2, which is thought to mediate its primary function at the cell surface, both ClC-3 and ClC-5 are stably expressed in endomembranes where they are thought to regulate the function of this organelle (39,41). Hence, the molecular components mediating localization and trafficking of ClC-3 and ClC-5 may be distinct from those mediating ClC-2 trafficking.…”

Human papillomavirus type 16 E6 protein interacts with cystic fibrosis transmembrane regulator-associated ligand and promotes E6-associated protein-mediated ubiquitination and proteasomal degradation

“…Overexpressed CAL decreases the half-life of mature CFTR by facilitating lysosomal degradation to reduce its plasma membrane expression (Cheng et al, 2002(Cheng et al, , 2004. CAL is also associated with targeting of other plasma membrane proteins such as Wnt receptors, Frizzled 5 and 8 (Yao et al, 2001), an EGF receptor family, CALEB/NGC (Hassel et al, 2003) and a chloride channel protein, ClC-3B (Gentzsch et al, 2003). It is supposed that CAL takes part in their intracellular trafficking, which was evidenced by interaction with a Q-SNARE protein, syntaxin 6 (Charest et al, 2001), and a small GTPase, TC10 regulating the translocation of the insulin-stimulated glucose transporter, GLUT4 to plasma membrane (Chiang et al, 2001;Neudauer et al, 2001).…”

Alterations in the regulatory volume decrease (RVD) and swelling-activated Cl-current associated with neuroendocrine differentiation of prostate cancer epithelial cells

“…These results prompted us to conclude that ClC-3 may be a part of endogenous VRAC per se or, given the evidence on possible intracellular ClC-3 location (e.g. Li et al 2002, Gentzsch et al 2003, a part of the molecular machinery involved in VRAC activation/ regulation in LNCaP cells. Moreover, the fact that the elevation of endogenous levels of ClC-3 protein in response to NE-differentiating regimens was paralleled by the enhancement of I Cl,swell not only provided an additional strong argument for a causal link between ClC-3 expression and VRAC function, but also suggested that NE differentiation modulates I Cl,swell by affecting ClC-3 content.…”