Spatial protein quality control requires a functional GET pathway to prevent proteotoxicity
- 1Marquette University
Abstract
The proper management of misfolded proteins is an essential biological process that is required for the survival of all organisms. Previous work has demonstrated that misfolded proteins can be spatially sequestered into membrane-less compartments to facilitate their degradation. Soluble cytoplasmic misfolded proteins are sequestered in the juxtanuclear quality control compartment (JUNQ), and insoluble cytoplasmic misfolded proteins are sequestered into the insoluble protein deposit (IPOD). It is still unknown if there are upstream targeting pathways necessary for regulating JUNQ and IPOD formation. Here we investigated the role of ER targeting on JUNQ and IPOD formation. We find that the GET pathway is necessary for JUNQ formation. Inefficiencies in the GET pathway contribute to premature IPOD formation, and a defective GET pathway inhibits JUNQ formation altogether. Notably, we find the role of the GET pathway in JUNQ formation is required for cell survival and loss of GET pathway function is only toxic under proteotoxic stress. Overall, we identify a new role for the GET pathway in regulating spatial PQC and demonstrate that spatial quality control is essential for cell health and survival.
Related
- Blast fungus unconventional effector secretion sorting requires pre-Golgi compartment protein MoGrh1
- Routing Misfolded Proteins through the Multivesicular Body (MVB) Pathway Protects against Proteotoxicity
- Apigenin Improves Healthspan and Protects Against Alzheimer's Disease-Associated Proteotoxicity in C. elegans
- CUBE: Multimodal Representation Learning Reveals Biological Structure Across Histomorphology, Spatial Protein Phenotypes, and Transcriptome-Associated Signals
- MorphoProt: RNA-Conditioned Integration of Multiscale Histology for Spatial Protein Inference
BibTeX
@misc{langridge2026spatial,
title = {{Spatial protein quality control requires a functional GET pathway to prevent proteotoxicity}},
author = {C. A. Langridge and E. M. Sontag},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.759444},
url = {https://www.biorxiv.org/content/10.64898/2026.10.15.759444v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Spatial protein quality control requires a functional GET pathway to prevent proteotoxicity
AU - C. A. Langridge
AU - E. M. Sontag
PY - 2026
DA - 2026/10/15
PB - bioRxiv
DO - 10.64898/2026.10.15.759444
UR - https://www.biorxiv.org/content/10.64898/2026.10.15.759444v1
AB - The proper management of misfolded proteins is an essential biological process that is required for the survival of all organisms. Previous work has demonstrated that misfolded proteins can be spatially sequestered into membrane-less compartments to facilitate their degradation. Soluble cytoplasmic misfolded proteins are sequestered in the juxtanuclear quality control compartment (JUNQ), and insoluble cytoplasmic misfolded proteins are sequestered into the insoluble protein deposit (IPOD). It is still unknown if there are upstream targeting pathways necessary for regulating JUNQ and IPOD formation. Here we investigated the role of ER targeting on JUNQ and IPOD formation. We find that the GET pathway is necessary for JUNQ formation. Inefficiencies in the GET pathway contribute to premature IPOD formation, and a defective GET pathway inhibits JUNQ formation altogether. Notably, we find the role of the GET pathway in JUNQ formation is required for cell survival and loss of GET pathway function is only toxic under proteotoxic stress. Overall, we identify a new role for the GET pathway in regulating spatial PQC and demonstrate that spatial quality control is essential for cell health and survival.
ER -