N-terminal Trimming Supports Proteostasis Under Secretory Protein Mislocalization Stress
- 1University of California, Riverside
Abstract
Secretory proteins that fail to enter the endoplasmic reticulum (ER) are mislocalized to the cytosol, where they threaten cellular proteostasis. How cells manage these mislocalized proteins remains poorly understood. Here, we show that inefficient Sec61 translocon activity induces a transcriptional stress response, which is enhanced by blocking NRF-1-dependent adaptation of proteasomal capacity. To maintain proteasomal capacity, thermodynamically stable mislocalized proteins persist in the cytosol of HepG2 and HEK293T cells, while mislocalized proteins that are inherently more aggregation-prone are preferentially ubiquitinated and degraded. This triaging process is accomplished through N-terminal trimming of the signal sequence of thermodynamically stable proteins, which simultaneously reduces their aggregation and prevents proteasomal degradation. These findings reveal a stability-dependent cytosolic triaging mechanism that matches substrate burden to proteasome capacity when ER import is challenged.
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BibTeX
@misc{castellanos2026nterminal,
title = {{N-terminal Trimming Supports Proteostasis Under Secretory Protein Mislocalization Stress}},
author = {J. P. Castellanos and K. K. Nguyen and Q. Lin and Z. Lyu and Z. Yang and F. Sarwono and J. C. Gonzalez and W. Nguyen and L. T. Huynh and C. Canizal and P. Satpute-Krishnan and W. Q. Shi and J. C. Genereux},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.756067},
url = {https://www.biorxiv.org/content/10.64898/2026.10.13.756067v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - N-terminal Trimming Supports Proteostasis Under Secretory Protein Mislocalization Stress
AU - J. P. Castellanos
AU - K. K. Nguyen
AU - Q. Lin
AU - Z. Lyu
AU - Z. Yang
AU - F. Sarwono
AU - J. C. Gonzalez
AU - W. Nguyen
AU - L. T. Huynh
AU - C. Canizal
AU - P. Satpute-Krishnan
AU - W. Q. Shi
AU - J. C. Genereux
PY - 2026
DA - 2026/10/13
PB - bioRxiv
DO - 10.64898/2026.10.13.756067
UR - https://www.biorxiv.org/content/10.64898/2026.10.13.756067v1
AB - Secretory proteins that fail to enter the endoplasmic reticulum (ER) are mislocalized to the cytosol, where they threaten cellular proteostasis. How cells manage these mislocalized proteins remains poorly understood. Here, we show that inefficient Sec61 translocon activity induces a transcriptional stress response, which is enhanced by blocking NRF-1-dependent adaptation of proteasomal capacity. To maintain proteasomal capacity, thermodynamically stable mislocalized proteins persist in the cytosol of HepG2 and HEK293T cells, while mislocalized proteins that are inherently more aggregation-prone are preferentially ubiquitinated and degraded. This triaging process is accomplished through N-terminal trimming of the signal sequence of thermodynamically stable proteins, which simultaneously reduces their aggregation and prevents proteasomal degradation. These findings reveal a stability-dependent cytosolic triaging mechanism that matches substrate burden to proteasome capacity when ER import is challenged.
SN - 2692-8205
ER -