Cargando…

Neurodegeneration-associated mutant TREM2 proteins abortively cycle between the ER and ER–Golgi intermediate compartment

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein expressed on microglia within the brain. Several rare mutations in TREM2 cause an early-onset form of neurodegeneration when inherited homozygously. Here we investigate how these mutations affect the intracellular tr...

Descripción completa

Detalles Bibliográficos
Autores principales: Sirkis, Daniel W., Aparicio, Renan E., Schekman, Randy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620379/
https://www.ncbi.nlm.nih.gov/pubmed/28768830
http://dx.doi.org/10.1091/mbc.E17-06-0423
_version_ 1783267574587326464
author Sirkis, Daniel W.
Aparicio, Renan E.
Schekman, Randy
author_facet Sirkis, Daniel W.
Aparicio, Renan E.
Schekman, Randy
author_sort Sirkis, Daniel W.
collection PubMed
description Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein expressed on microglia within the brain. Several rare mutations in TREM2 cause an early-onset form of neurodegeneration when inherited homozygously. Here we investigate how these mutations affect the intracellular transport of TREM2. We find that most pathogenic TREM2 mutant proteins fail to undergo normal maturation in the Golgi complex and show markedly reduced cell-surface expression. Prior research has suggested that two such mutants are retained in the endoplasmic reticulum (ER), but we find, using a cell-free coat protein complex II (COPII) vesicle budding reaction, that mutant TREM2 is exported efficiently from the ER. In addition, mutant TREM2 becomes sensitive to cleavage by endoglycosidase D under conditions that inhibit recycling to the ER, indicating that it normally reaches a post-ER compartment. Maturation-defective TREM2 mutants are also efficiently bound by a lectin that recognizes O-glycans added in the ER–Golgi intermediate compartment (ERGIC) and cis-Golgi cisterna. Finally, mutant TREM2 accumulates in the ERGIC in cells depleted of COPI. These results indicate that efficient ER export is not sufficient to enable normal cell-surface expression of TREM2. Moreover, our findings suggest that the ERGIC may play an underappreciated role as a quality-control center for mutant and/or malformed membrane proteins.
format Online
Article
Text
id pubmed-5620379
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-56203792017-12-16 Neurodegeneration-associated mutant TREM2 proteins abortively cycle between the ER and ER–Golgi intermediate compartment Sirkis, Daniel W. Aparicio, Renan E. Schekman, Randy Mol Biol Cell Articles Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein expressed on microglia within the brain. Several rare mutations in TREM2 cause an early-onset form of neurodegeneration when inherited homozygously. Here we investigate how these mutations affect the intracellular transport of TREM2. We find that most pathogenic TREM2 mutant proteins fail to undergo normal maturation in the Golgi complex and show markedly reduced cell-surface expression. Prior research has suggested that two such mutants are retained in the endoplasmic reticulum (ER), but we find, using a cell-free coat protein complex II (COPII) vesicle budding reaction, that mutant TREM2 is exported efficiently from the ER. In addition, mutant TREM2 becomes sensitive to cleavage by endoglycosidase D under conditions that inhibit recycling to the ER, indicating that it normally reaches a post-ER compartment. Maturation-defective TREM2 mutants are also efficiently bound by a lectin that recognizes O-glycans added in the ER–Golgi intermediate compartment (ERGIC) and cis-Golgi cisterna. Finally, mutant TREM2 accumulates in the ERGIC in cells depleted of COPI. These results indicate that efficient ER export is not sufficient to enable normal cell-surface expression of TREM2. Moreover, our findings suggest that the ERGIC may play an underappreciated role as a quality-control center for mutant and/or malformed membrane proteins. The American Society for Cell Biology 2017-10-01 /pmc/articles/PMC5620379/ /pubmed/28768830 http://dx.doi.org/10.1091/mbc.E17-06-0423 Text en © 2017 Sirkis et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Sirkis, Daniel W.
Aparicio, Renan E.
Schekman, Randy
Neurodegeneration-associated mutant TREM2 proteins abortively cycle between the ER and ER–Golgi intermediate compartment
title Neurodegeneration-associated mutant TREM2 proteins abortively cycle between the ER and ER–Golgi intermediate compartment
title_full Neurodegeneration-associated mutant TREM2 proteins abortively cycle between the ER and ER–Golgi intermediate compartment
title_fullStr Neurodegeneration-associated mutant TREM2 proteins abortively cycle between the ER and ER–Golgi intermediate compartment
title_full_unstemmed Neurodegeneration-associated mutant TREM2 proteins abortively cycle between the ER and ER–Golgi intermediate compartment
title_short Neurodegeneration-associated mutant TREM2 proteins abortively cycle between the ER and ER–Golgi intermediate compartment
title_sort neurodegeneration-associated mutant trem2 proteins abortively cycle between the er and er–golgi intermediate compartment
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620379/
https://www.ncbi.nlm.nih.gov/pubmed/28768830
http://dx.doi.org/10.1091/mbc.E17-06-0423
work_keys_str_mv AT sirkisdanielw neurodegenerationassociatedmutanttrem2proteinsabortivelycyclebetweentheerandergolgiintermediatecompartment
AT apariciorenane neurodegenerationassociatedmutanttrem2proteinsabortivelycyclebetweentheerandergolgiintermediatecompartment
AT schekmanrandy neurodegenerationassociatedmutanttrem2proteinsabortivelycyclebetweentheerandergolgiintermediatecompartment