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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2017
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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 |
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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 |
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