# Role of very long chain fatty acids in protein quality control and membrane homeostasis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $358,000

## Abstract

Project Summary/Abstract
 Cells have developed complex stress responses to identify and eliminate misfolded proteins. An exciting
development in recent years has been the recognition that lipid homeostasis is critical for protein quality control.
The Unfolded Protein Response (UPR) senses misfolded proteins in the endoplasmic reticulum and orchestrates
a broad program of cellular remodeling to address this threat. Various defects in lipid metabolism trigger the
UPR, and the UPR in turn controls the expression of some lipid metabolic genes. Furthermore, in contrast to the
canonical luminal signaling mechanism for misfolded proteins, recent work indicates the presence of a second
sensor pathway that detects defects in the ER membrane ("bilayer stress"). The functional properties of
membranes (e.g. thickness, fluidity, curvature) are largely determined by their compositions. Far from early
conceptions of membranes as static or inert structures, we now understand that membranes are highly dynamic
and capable of altering their compositions in response to changing cellular conditions/needs. This proposal
focuses on a poorly understood group of lipids known as very long chain fatty acids (VLCFAs) which are relatively
unabundant but perform critical functions. We hypothesize that VLCFAs play key roles in protein quality control
and membrane homeostasis. To inhibit VLCFA utilization, we have studied a mutant of the major VLCFA CoA
synthetase, Fat1. Our preliminary data indicate that Fat1 plays an important role in ER homeostasis, and its loss
triggers compensatory induction of the UPR. To understand the basis for this effect, we carried out a mass
spectrometry-based lipidomic analysis. Remarkably, the fat1Δ mutant showed a dramatic increase in membrane
saturation which is a known inducer of the UPR. This effect is mediated, at least in part, via partial loss of function
of Ole1, the sole fatty acyl desaturase in yeast. In Aim 1, we will determine the mechanism by which VLCFAs
regulate membrane homeostasis and the UPR. Recent data implicate membrane saturation as a key determinant
of alpha-synuclein toxicity, which is responsible for Parkinson's disease. Our data indicate that Fat1 is an
important regulator of synuclein toxicity. In Aim 2, we will determine mechanism by which VLCFAs regulate
synuclein toxicity in yeast and Drosophila. Completion of this proposal is expected to provide both basic and
disease-oriented mechanistic insight into this emerging but fundamental area of cell biology.

## Key facts

- **NIH application ID:** 10051111
- **Project number:** 1R01GM135337-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** John W Hanna
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $358,000
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051111

## Citation

> US National Institutes of Health, RePORTER application 10051111, Role of very long chain fatty acids in protein quality control and membrane homeostasis (1R01GM135337-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10051111. Licensed CC0.

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