Preferential association with ClC-3 permits sorting of ClC-4 into endosomal compartments.
J Biol Chem
; 292(46): 19055-19065, 2017 11 17.
Article
em En
| MEDLINE
| ID: mdl-28972156
ABSTRACT
ClC-4 is an intracellular Cl-/H+ exchanger that is highly expressed in the brain and whose dysfunction has been linked to intellectual disability and epilepsy. Here we studied the subcellular localization of human ClC-4 in heterologous expression systems. ClC-4 is retained in the endoplasmic reticulum (ER) upon overexpression in HEK293T cells. Co-expression with distinct ClC-3 splice variants targets ClC-4 to late endosome/lysosomes (ClC-3a and ClC-3b) or recycling endosome (ClC-3c). When expressed in cultured astrocytes, ClC-4 sorted to endocytic compartments in WT cells but was retained in the ER in Clcn3-/- cells. To understand the virtual absence of ER-localized ClC-4 in WT astrocytes, we performed association studies by high-resolution clear native gel electrophoresis. Although other CLC channels and transporters form stable dimers, ClC-4 was mostly observed as monomer, with ClC-3-ClC-4 heterodimers being more stable than ClC-4 homodimers. We conclude that unique oligomerization properties of ClC-4 permit regulated targeting of ClC-4 to various endosomal compartment systems via expression of different ClC-3 splice variants.
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MEDLINE
Assunto principal:
Endossomos
/
Canais de Cloreto
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article