# Exploring New Players in Proteostasis

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $718,790

## Abstract

Maintaining protein homeostasis, also known as proteostasis, is fundamentally important for all processes in
biology. It is therefore not surprising, that cells contain an entire fleet of chaperones and proteases, which
are tasked to correctly fold and target nascent proteins, prevent unsolicited protein misfolding and protect
proteins against irreversible aggregation. Unfortunately, however, disturbances in the activity or composition
of the proteostasis network do occur, and can be devastating, particularly in their relationship to amyloid-
related protein folding diseases, including Alzheimer’s and Parkinson’s disease. My lab focuses on two
different mechanisms that are involved in maintaining protein homeostasis. My first major project centers on
the functional activity of polyphosphate, a highly conserved polymer composed of long chains of phospho-
anhydride bonded phosphates. Previous work from our lab demonstrated that polyP shares many features
with protein chaperones, including its ability to prevent stress-specific protein aggregation, and to protect
neuronal cells against amyloid toxicity by modulating disease-associated amyloid fibril formation. Most
recently, we added a new function to polyP’s stress-protective repertoire by demonstrating that it undergoes
liquid-liquid phase transitions with nucleoid-associated proteins, and in doing so, contributes to the silencing
of genetic mobile elements in bacteria. We will now use a multipronged cell biological, biochemical and cryo-
EM-based structural approach to i) understand the parameters that drives polyP to interact with proteins in
these multiple different capacities, ii) test the exciting hypothesis, based on two recently solved cryoEM
structures of patient-derived fibrils, that polyP is a physiologically relevant modulator of amyloidogenic
processes, and iii) investigate polyP’s newly identified role as a critical component of bacterial
heterochromatin. The second major research arm in my lab is centered on the hypothesis that histone-based
epigenetic modifications constitute an important but vastly understudied mechanism that acts in regulating
protein homeostasis. We posit that these modifications can affect proteostasis in the short term, long-term
and potentially even trans-generationally. We will focus on the inheritable histone modification H3K4me3,
whose global reduction has been shown by us and others to increase stress gene expression, improve stress
resistance and protect organisms against amyloid-related toxicity. Our major goals are to explore the
mechanism of how global changes in H3K4me3 levels can exert these consequential effects on proteostasis
in general and amyloidogenic processes in particular. Our studies have the potential of adding entirely new
layers of mechanisms to the regulation of protein homeostasis, and will aid in achieving the overarching goal
of identifying the major players guarding the proteome and understanding how they work.

## Key facts

- **NIH application ID:** 10405701
- **Project number:** 2R35GM122506-06
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ursula H. Jakob
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $718,790
- **Award type:** 2
- **Project period:** 2017-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405701

## Citation

> US National Institutes of Health, RePORTER application 10405701, Exploring New Players in Proteostasis (2R35GM122506-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10405701. Licensed CC0.

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