Year: 2026
Type: preprint
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.
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Awards: MRI: Acquisition of a Hybrid Supercritical Chromatography, High-Pressure Chromatograph, Quadrupole-Time-of-Flight Mass Spectrometer (SFC/UHPLC Q-ToF/MS), Louis Stokes STEM Pathways and Research Alliance: California Louis Stokes Alliance for Minority Participation, G5639751648, G645726058, G8839305273
OpenAlex ID: W7222265401