ER-associated degradation and disposal of misfolded GPI-anchored proteins in Trypanosoma brucei
File(s)
Published version
Author(s)
Tiengwe, CW
Koeller, Carolina
Bangs, James
Type
Journal Article
Abstract
Misfolded secretory proteins are retained by endoplasmic reticulum quality control (ERQC) and degraded in the proteasome by ER-associated degradation (ERAD). However, in yeast and mammals, misfolded glycosylphosphatidylinositol (GPI)-anchored proteins are preferentially degraded in the vacuole/lysosome. We investigate this process in the divergent eukaryotic pathogen Trypanosoma brucei using a misfolded GPI-anchored subunit (HA:E6) of the trypanosome transferrin receptor. HA:E6 is N-glycosylated and GPI-anchored and accumulates in the ER as aggregates. Treatment with MG132, a proteasome inhibitor, generates a smaller protected polypeptide (HA:E6*), consistent with turnover in the proteasome. HA:E6* partitions between membrane and cytosol fractions, and both pools are proteinase K-sensitive, indicating cytosolic disposition of membrane-associated HA:E6*. HA:E6* is de-N-glycosylated and has a full GPI-glycan structure from which dimyristoylglycerol has been removed, indicating that complete GPI removal is not a prerequisite for proteasomal degradation. However, HA:E6* is apparently not ubiquitin-modified. The trypanosome GPI anchor is a forward trafficking signal; thus the dynamic tension between ERQC and ER exit favors degradation by ERAD. These results differ markedly from the standard eukaryotic model systems and may indicate an evolutionary advantage related to pathogenesis.
Date Issued
2018-10-01
Date Acceptance
2018-07-23
Citation
Molecular Biology of the Cell, 2018, 29 (20), pp.2359-2507
ISSN
1059-1524
Publisher
American Society for Cell Biology
Start Page
2359
End Page
2507
Journal / Book Title
Molecular Biology of the Cell
Volume
29
Issue
20
Copyright Statement
© 2018 Tiengwe, Koeller, and Bangs. 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).
Subjects
06 Biological Sciences
11 Medical And Health Sciences
Developmental Biology
Publication Status
Published
Date Publish Online
2018-09-27