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

Abstract:

: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.

journal_name

Mol Biol Cell

authors

Sirkis DW,Aparicio RE,Schekman R

doi

10.1091/mbc.E17-06-0423

subject

Has Abstract

pub_date

2017-10-01 00:00:00

pages

2723-2733

issue

20

eissn

1059-1524

issn

1939-4586

pii

mbc.E17-06-0423

journal_volume

28

pub_type

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