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

Abstract 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 endo...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Praseetha Kizhakkedath, Anne John, Lihadh Al-Gazali, Bassam R. Ali
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/42f46ad140864e1dae302a40dbeda623
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:42f46ad140864e1dae302a40dbeda623
record_format	dspace
spelling	oai:doaj.org-article:42f46ad140864e1dae302a40dbeda6232021-12-02T15:09:04ZDegradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome10.1038/s41598-017-19053-82045-2322https://doaj.org/article/42f46ad140864e1dae302a40dbeda6232018-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-19053-8https://doaj.org/toc/2045-2322Abstract 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.Praseetha KizhakkedathAnne JohnLihadh Al-GazaliBassam R. AliNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Praseetha Kizhakkedath Anne John Lihadh Al-Gazali Bassam R. Ali Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome
description	Abstract 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.
format	article
author	Praseetha Kizhakkedath Anne John Lihadh Al-Gazali Bassam R. Ali
author_facet	Praseetha Kizhakkedath Anne John Lihadh Al-Gazali Bassam R. Ali
author_sort	Praseetha Kizhakkedath
title	Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome
title_short	Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome
title_full	Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome
title_fullStr	Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome
title_full_unstemmed	Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome
title_sort	degradation routes of trafficking-defective vldlr mutants associated with dysequilibrium syndrome
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/42f46ad140864e1dae302a40dbeda623
work_keys_str_mv	AT praseethakizhakkedath degradationroutesoftraffickingdefectivevldlrmutantsassociatedwithdysequilibriumsyndrome AT annejohn degradationroutesoftraffickingdefectivevldlrmutantsassociatedwithdysequilibriumsyndrome AT lihadhalgazali degradationroutesoftraffickingdefectivevldlrmutantsassociatedwithdysequilibriumsyndrome AT bassamrali degradationroutesoftraffickingdefectivevldlrmutantsassociatedwithdysequilibriumsyndrome
_version_	1718387932872572928

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

Ejemplares similares