# Regulation of mRNA decay and metabolism during endoplasmic reticulum stress

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $307,355

## Abstract

Project summary
 The capacity of the endoplasmic reticulum (ER) to fold and process proteins is maintained
through a collection of signaling pathways termed the Unfolded Protein Response (UPR). The UPR is
essential for development and differentiation of secretory cells and modulates a variety of human
diseases including diabetes, cancer, and Alzheimer’s disease. The overall goal of this proposal is to
understand the effects of the UPR in mammalian cells, focusing on two poorly understood aspects of its
function: the regulation of mRNA decay and glucose metabolism.
 Activation of the mammalian UPR leads to the highly specific degradation of membrane-
associated mRNAs. While this pathway has been observed in mice and is well-understood at the
molecular level, its cell biological function is not clear. This proposal aims to understand the effects of
this mRNA degradation pathway by focusing on its main target, Blos1. Both activation of the UPR and
depletion of Blos1 by RNA interference lead to the perinuclear accumulation of lysosomes and the
stabilization of Epidermal Growth Factor Receptor (EFGR) at the plasma membrane. The proposed
research will use cultured cells to test the mechanism and consequences of these phenotypes, with the
underlying hypothesis that lysosome re-positioning increases plasma membrane protein recycling,
allowing cells to maintain surface protein activities by when trafficking from the ER is disrupted.
 The second goal of this proposal is to understand the interplay between the UPR and the
metabolism of glucose. During UPR activation, cells switch their metabolism to aerobic glycolysis. This
metabolic signature is also a hallmark of cancer cells, suggesting a role for the UPR in cancer
metabolism. Hes1, a transcriptional repressor involved in differentiation, quiescence, and cancer, is a
novel UPR target that down-regulates a key enzyme in the TCA cycle. This proposal will test the
mechanism of metabolic regulation by the UPR, both in cells subjected to chemicals disrupting ER
function and in cells differentiating into mature, collagen-secreting osteoblasts. The proposed
experiments will then test two hypotheses regarding why the UPR regulates metabolism in this way: (a)
that the reduction in oxidative phosphorylation protects cells from over-production of reactive oxygen
species when ER oxidative protein folding is increased, and (b) that the upregulation of glycolysis is
necessary to provide intermediates for increased glycoprotein and membrane production.

## Key facts

- **NIH application ID:** 10005415
- **Project number:** 5R35GM119540-05
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** JULIE HOLLIEN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $307,355
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005415

## Citation

> US National Institutes of Health, RePORTER application 10005415, Regulation of mRNA decay and metabolism during endoplasmic reticulum stress (5R35GM119540-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10005415. Licensed CC0.

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