CHOP promotes the transition to chronic integrated stress response signaling with suppression of hepatocyte identity

Theo F. Velarde; Kaihua Liu; Zewei Zhang; Reed C. Adajar; Chaoxian Zhao; Huojun Cao; D. Thomas Rutkowski

doi:10.64898/2026.05.13.724984

Back

CHOP promotes the transition to chronic integrated stress response signaling with suppression of hepatocyte identity

Preprint

Open access

CHOP promotes the transition to chronic integrated stress response signaling with suppression of hepatocyte identity

Theo F. Velarde, Kaihua Liu, Zewei Zhang, Reed C. Adajar, Chaoxian Zhao, Huojun Cao and D. Thomas Rutkowski

bioRxiv

Cold Spring Harbor Laboratory Preprints

05/15/2026

DOI: 10.64898/2026.05.13.724984

PMCID: PMC13192784

PMID: 42182362

Files and links (1)

url

https://doi.org/10.64898/2026.05.13.724984View

Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

The transcription factor CHOP promotes cell death during ER stress, but it is strongly induced even by moderate stresses that do not result in appreciable cell death. Its role during less severe stresses—especially in intact tissues in vivo —is poorly understood. Here, we both deleted and restored CHOP specifically in hepatocytes and challenged animals with ER stress in vivo . We found that CHOP influenced stress-dependent hepatocyte gene expression through two previously unappreciated mechanisms. It directly suppressed the expression of transcriptional master regulators of hepatocyte identity and metabolism. And more broadly, it exacerbated ER stress through the promotion of protein synthesis, which led to persistent activation of the integrated stress response (ISR) despite dephosphorylation of eIF2α. This shift to second-phase ISR signaling was phenocopied by deletion of the protective UPR sensor ATF6α, suggesting that it reflects a transition from an acute stress response to a chronic one. Our findings show that CHOP augments the capacity of the ISR and UPR to continue to mount a protective response even after eIF2α phosphorylation has been suppressed. In vivo , where ISR signaling intersects with hepatocyte gene regulatory networks, this transition favors lipid dysregulation, highlighting a pathway through which CHOP impacts tissue function independent of cell death.

Details

Title: Subtitle: CHOP promotes the transition to chronic integrated stress response signaling with suppression of hepatocyte identity
Creators: Theo F. Velarde - University of Iowa
Kaihua Liu - University of Iowa
Zewei Zhang - University of Iowa
Reed C. Adajar - University of Iowa
Chaoxian Zhao - Shanghai Jiao Tong University
Huojun Cao - University of Iowa
D. Thomas Rutkowski - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.64898/2026.05.13.724984
PMID: 42182362
PMCID: PMC13192784
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory Preprints
Language: English
Date posted: 05/15/2026
Academic Unit: Anatomy and Cell Biology; Endodontics; Orthopedics and Rehabilitation; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9985164731802771

Metrics

1 Record Views