# Regulating the Unfolded Protein Response in Yeast

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN MILWAUKEE · 2020 · $334,336

## Abstract

The unfolded protein response (UPR) is a strategy to increase the protein folding capacity of cells and
to maintain the proteostasis network (PN). If this strategy fails, unfolded proteins aggregate causing many
human diseases, including diabetes, arthritis and certain cancers. Thus, molecular understanding of the
UPR or PN is important to develop new approaches to prevent/reverse the protein folding diseases.
 Ire1, an endoplasmic reticulum (ER)-resident protein, activates the UPR from yeast to humans. Ire1
activates production of the protein Xbp1 in human cells or Hac1 in yeast cells by processing (cytoplasmic
splicing)theirtranslationallyrepressedmRNAs.Hac1/Xbp1thenbindstoacis-regulatoryUPRelement
(UPRE) and induces expression of folding enzymes and chaperons (e.g., yeast Kar2 or human BiP).
Though Hac1 is thought to induce the Kar2 in yeast, it has been shown that the Kar2 level is significantly
increased when Hac1 or Ire1 protein null strain is subjected to an ER stress. We found that the Kar2 level
was decreased in the strain lacking a new UPR modulator Kin2 and remained unchanged even when the
Hac1 protein level was reduced in a strain lacking the kinase Pkh1. These observations suggest that other
sensors or components might activate the yeast UPR. To identify new components modulating the yeast
UPR, we conducted a genetic screen with gene-deletion strains of the yeast Saccharomyces cerevisiae
and found that the amount of Hac1 or UPRE-driven lacZ reporter was significantly reduced in a few strains
each lacking a single protein. These proteins include Vps15 (an ortholog of human phosphoinositide-3-
kinase (PI3K) regulatory subunit), Bmh2 (an ortholog of human 14-3-3 protein) and Yhr097C (a previously
uncharacterized protein and hereafter referred to as Pdp2) and Cdc42 (a conserved Rho-like GTPase).
These proteins (Kin2, Vps15, Bmh2, Cdc42 and Pdp2) have been shown to play important roles in distinct
cellular processes, and our results reveal their novel role in the UPR.
 We also obtained data that provided insights on Kin2 activation, interactions among the new UPR
regulators, and the involvement of Vps15 in the UPR. Here, we will test three hypotheses: (1) Cdc42 and
Bmh2 bind to Kin2 releasing auto-inhibition and enabling an upstream kinase to phosphorylate/activate
the Kin2 kinase domain (KD); (2) Pdp2 activates HAC1 mRNA translation by interacting with its 3’-
untranslated region; and (3) Vps15 kinase augments the Hac1-mediated UPR, or alternatively promotes
the UPR by phosphorylating a substrate. The insights on the fundamental mechanism of the UPR
obtained from these studies in yeast will provide new avenues of investigation for the human UPR leading
to the possible identification of new pathway components to target and treat protein-folding diseases.

## Key facts

- **NIH application ID:** 9986818
- **Project number:** 5R01GM124183-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN MILWAUKEE
- **Principal Investigator:** Madhusudan Dey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $334,336
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986818

## Citation

> US National Institutes of Health, RePORTER application 9986818, Regulating the Unfolded Protein Response in Yeast (5R01GM124183-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9986818. Licensed CC0.

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