Impaired trafficking of the very low density lipoprotein receptor caused by missense mutations associated with dysequilibrium syndrome

Kizhakkedath, Praseetha; Loregger, Anke; John, Anne; Bleijlevens, Boris; Al-Blooshi, Ali S.; Alhosani, Ahmed; Al-Nuaimi, Ahmed M.; Zelcer, Noam; Ali, Bassam R.

doi:10.1016/j.bbamcr.2014.08.013

Cited by 10 publications

(11 citation statements)

References 43 publications

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“…The three residues (D487, D521, and C706) mutated in VLDLR in DES are also conserved in the LDLR (D445, D482, C667). We have reported previously that the pathogenic missense mutations in VLDLR result in the ER retention and loss‐of‐function of the mutants . The corresponding VLDLR mutants were found to be aggregation‐prone and found to exert ER stress and are degraded by the ubiquitin‐proteasome pathway .…”

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confidence: 99%

Endoplasmic reticulum quality control of LDLR variants associated with familial hypercholesterolemia

et al. 2019

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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.

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Endoplasmic reticulum quality control of LDLR variants associated with familial hypercholesterolemia

et al. 2019

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“…The precursor form matures into the fully glycosylated form within 6 h and the mature wild type VLDLR receptor has been reported to have a half-life of ~24 h 19 . We have reported previously that none of the three missense mutants analyzed in this study, attain Endoglycosidase H resistant advanced glycosylation specific to Golgi 8 . After 24 h of cycloheximide chase, only the mature glycosylated form was visible in the immunoblots of wild type (Fig.…”

Section: Resultsmentioning

confidence: 56%

“…Previously we have reported that missense mutants of the VLDLR (D487Y, D521H and C706F) receptor were transport deficient and dysfunctional 8 . To analyze the possibility of increased intracellular degradation of VLDLR mutants, turn-over rates of the three missense mutants, D487Y, D521H, C706Y and wild type VLDLR (WT) receptor were determined by cycloheximide translation shut-off assay in HEK-293 cells overexpressing the wild type or mutants.…”

Section: Resultsmentioning

confidence: 99%

“…In neurons, VLDLR is a receptor for Reelin and an integral part of the Reelin signaling pathway that directs the migration of neuroblasts during embryonic brain development 7 . Previously we have reported that three missense mutations in VLDLR (c.1459 G > T; p.D487Y, c.1561 G > C; p.D521H and c.2117 G > T; p.C706F), associated with DES, inhibit the cell surface trafficking of the receptor and thus interrupt binding to its ligand Reelin 8 .…”

Section: Introductionmentioning

confidence: 99%

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Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome

Kizhakkedath

John

Ali

2018

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Low density lipoprotein receptor (LDLR) family members are involved in signaling in the developing brain. Previously we have reported that missense mutations in the Very Low Density Lipoprotein Receptor gene (VLDLR), causing Dysequilibrium syndrome (DES), disrupt ligand-binding, due to endoplasmic reticulum (ER) retention of the mutants. We explored the degradation routes of these VLDLR mutants in cultured cells. Our results indicate that VLDLR mutants are retained in the ER for prolonged periods which could be facilitated by association with the ER-resident chaperone calnexin. The mutants were prone to aggregation and capable of eliciting ER stress. The VLDLR mutants were found to be degraded predominantly by the proteasomal pathway, since ubiquitinated VLDLR was found to accumulate in response to proteasomal inhibition. Further, the mutants were found to interact with the ER degradation adaptor protein SEL1L. The degradation of VLDLR wild type and mutant were delayed in CRISPR/Cas9 edited SEL1L knock-out cells which was reversed by exogenous expression of SEL1L. In summary, ER retention of pathogenic VLDLR mutants involves binding to calnexin, elevated ER stress, and delayed degradation which is dependent on SEL1L. Since core LDLR family members share common structural domains, common mechanisms may be involved in their ER processing.

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“…Many membrane and secretory proteins that fail to conform to the ER quality control (ERQC) are dislocated into the cytosol and degraded by the proteasome by a process termed as ER-associated degradation (ERAD) ( Vembar and Brodsky, 2008 ; Ruggiano et al, 2014 ; Sun and Brodsky, 2019 ). Misfolded proteins can still retain their function and premature ERAD of mutant misfolded proteins is accounted for the cellular pathogenesis of several congenital disorders ( Ward et al, 1995 ; Hume et al, 2009 ; Ali et al, 2011 ; Al-Kindi et al, 2014 ; Kizhakkedath et al, 2014 , 2019 ; John et al, 2015 ). Sometimes the quality control mechanisms fail to recognize folding-incompetent forms which leads to the accumulation of folding-intermediates in the ER, causing ER stress.…”

Section: Mechanisms Of Protein Quality Control and Proteostasis Regulmentioning

confidence: 99%

Proteostasis Regulation in the Endoplasmic Reticulum: An Emerging Theme in the Molecular Pathology and Therapeutic Management of Familial Hypercholesterolemia

et al. 2020

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Familial hypercholesterolemia (FH) is an autosomal genetic disease characterized by high serum low-density lipoprotein (LDL) content leading to premature coronary artery disease. The main genetic and molecular causes of FH are mutations in low-density lipoprotein receptor gene ( LDLR ) resulting in the non-clearance of LDL from the blood by hepatocytes and consequently the formation of plaques. LDLR is synthesized and glycosylated in the endoplasmic reticulum (ER) and then transported to the plasma membrane via Golgi. It is estimated that more than 50% of reported FH-causing mutations in LDLR result in misfolded proteins that are transport-defective and hence retained in ER. ER accumulation of misfolded proteins causes ER-stress and activates unfolded protein response (UPR). UPR aids protein folding, blocks further protein synthesis, and eliminates misfolded proteins via ER-associated degradation (ERAD) to alleviate ER stress. Various studies demonstrated that ER-retained LDLR mutants are subjected to ERAD. Interestingly, chemical chaperones and genetic or pharmacological inhibition of ERAD have been reported to rescue the transport defective mutant LDLR alleles from ERAD and restore their ER-Golgi transport resulting in the expression of functional plasma membrane LDLR. This suggests the possibility of pharmacological modulation of proteostasis in the ER as a therapeutic strategy for FH. In this review, we picture a detailed analysis of UPR and the ERAD processes activated by ER-retained LDLR mutants associated with FH. In addition, we discuss and critically evaluate the potential role of chemical chaperones and ERAD modulators in the therapeutic management of FH.

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Impaired trafficking of the very low density lipoprotein receptor caused by missense mutations associated with dysequilibrium syndrome

Cited by 10 publications

References 43 publications

Endoplasmic reticulum quality control of LDLR variants associated with familial hypercholesterolemia

Endoplasmic reticulum quality control of LDLR variants associated with familial hypercholesterolemia

Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome

Proteostasis Regulation in the Endoplasmic Reticulum: An Emerging Theme in the Molecular Pathology and Therapeutic Management of Familial Hypercholesterolemia

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