Routing Misfolded Proteins through the Multivesicular Body (MVB) Pathway Protects against Proteotoxicity
Abstract
The secretory pathway maintains multiple quality control checkpoints. Initially, endoplasmic reticulum-associated degradation pathways monitor protein folding to retain and eliminate aberrant products. Despite its broad client range, some molecules escape detection and traffic to Golgi membranes. There, a poorly understood mechanism termed Golgi quality control routes aberrant proteins for lysosomal/vacuolar degradation. To better understand Golgi quality control, we examined the processing of the obligate substrate Wsc1p. Misfolded Wsc1p does not use routes of typical vacuolar membrane proteins. Instead, it partitions into intralumenal vesicles of the multivesicular body (MVB) pathway, mediated by the E3 ubiquitin ligase Rsp5p. Its subsequent transport to the vacuolar lumen is essential for complete molecule breakdown. Surprisingly, the transport mode plays a second crucial function in neutralizing potential substrate toxicity. Eliminating the MVB sorting signal diverted molecules to the vacuolar limiting membrane, resulting in the generation of toxic by-products. These data demonstrate a new role of the MVB pathway in protein quality control.
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BibTeX
@article{wang2026routing,
title = {{Routing Misfolded Proteins through the Multivesicular Body (MVB) Pathway Protects against Proteotoxicity}},
author = {Songyu Wang and Guillaume Thibault and Davis T.W. Ng},
journal = {Journal of Biological Chemistry},
year = {2026},
month = sep,
doi = {10.1074/jbc.m111.233346},
url = {https://hal.science/hal-05770396v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Routing Misfolded Proteins through the Multivesicular Body (MVB) Pathway Protects against Proteotoxicity
AU - Songyu Wang
AU - Guillaume Thibault
AU - Davis T.W. Ng
PY - 2026
DA - 2026/09/30
JO - Journal of Biological Chemistry
DO - 10.1074/jbc.m111.233346
UR - https://hal.science/hal-05770396v1
AB - The secretory pathway maintains multiple quality control checkpoints. Initially, endoplasmic reticulum-associated degradation pathways monitor protein folding to retain and eliminate aberrant products. Despite its broad client range, some molecules escape detection and traffic to Golgi membranes. There, a poorly understood mechanism termed Golgi quality control routes aberrant proteins for lysosomal/vacuolar degradation. To better understand Golgi quality control, we examined the processing of the obligate substrate Wsc1p. Misfolded Wsc1p does not use routes of typical vacuolar membrane proteins. Instead, it partitions into intralumenal vesicles of the multivesicular body (MVB) pathway, mediated by the E3 ubiquitin ligase Rsp5p. Its subsequent transport to the vacuolar lumen is essential for complete molecule breakdown. Surprisingly, the transport mode plays a second crucial function in neutralizing potential substrate toxicity. Eliminating the MVB sorting signal diverted molecules to the vacuolar limiting membrane, resulting in the generation of toxic by-products. These data demonstrate a new role of the MVB pathway in protein quality control.
SN - 0021-9258
SN - 1083-351X
ER -