Open AccessEndoplasmic reticulum quality control of LDLR variants associated with familial hypercholesterolemia
Author(s) -
Kizhakkedath Praseetha,
John Anne,
AlSawafi Buthaina K.,
AlGazali Lihadh,
Ali Bassam R.
Publication year - 2019
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.12740
Subject(s) - ldl receptor , endoplasmic reticulum , familial hypercholesterolemia , mutant , mutation , biology , receptor , microbiology and biotechnology , unfolded protein response , gene , genetics , biochemistry , lipoprotein , cholesterol
Loss‐of‐function mutations in the low‐density lipoprotein receptor ( LDLR ) gene can cause familial hypercholesterolemia (FH), but detailed functional evidence for pathogenicity is limited to a few reported mutations. Here, we investigated the cellular pathogenic mechanisms of three mutations in LDLR causing FH, which are structurally identical to pathogenic mutations in the very low‐density lipoprotein receptor (VLDLR). Similar to the VLDLR mutants, LDLR mutants D482H and C667F were found to be localized to the ER, while D445E, which is a conserved amino acid change, did not affect the trafficking of the receptor to the plasma membrane, as confirmed by the N‐glycosylation profile. Although the ER‐retained mutant proteins were soluble, induction of ER stress was observed as indicated by spliced X‐box binding protein‐1 (XBP‐1) mRNA levels. The mutants were found to associate with ER quality control components, and their stability was enhanced by inhibitors of proteasome. Our results contribute to the growing list of transport‐deficient class II LDLR variants leading to FH and provide evidence for the involvement of endoplasmic reticulum‐associated degradation in their stability.