# A transmembrane Rab GTPase accelerating protein targeted to peroxisomes

> **NIH NIH SC2** · CALIFORNIA STATE UNIV SAN BERNARDINO · 2021 · $142,590

## Abstract

Project Summary
Understanding how cells adapt to stress and repair damage is one of the highest priorities in cell biology and
health research. The endoplasmic reticulum (ER) is a key source of lipid and proteins for building and
maintaining several organelles in cells, and in response to stimuli it is capable of directing resources into an
assortment of transport pathways. The signaling protein Ypt1/Rab1 is a Rab GTPase (Rab) that plays
essential roles in how the ER directs resources and executes quality control of damaged organelles including
mitochondria and peroxisomes. Our long-term goal is to understand the mechanisms for how lipid and protein
cargos are routed and re-routed to specific itineraries in response to cellular stimuli and stresses, which will
inform development of targeted therapeutic interventions to address diseases. We have found that the
GTPase accelerating protein Gyp8, an evolutionarily conserved but poorly understood negative regulator of
Ypt1/Rab1 signaling, localizes to the ER, peroxisomes and mitochondria and impinges on Ypt1 signaling. Our
central hypotheses are that Gyp8 functions to modulate Ypt1/Rab1 signaling in the early secretory pathway
(ER) and at non-secretory membranes (peroxisomes and mitochondria) that are subject to frequent damage
and quality control via Ypt1/Rab1-dependent selective autophagy. Also, since Gyp8 localizes to organelles
that commonly tether/dock to exchange materials in essential metabolic pathways, we predict that Gyp8
regulates Rab-dependent tethering interactions, particularly among organelles specialized for lipid storage and
metabolism. To test our central hypotheses and advance understanding of several membrane biogenesis
pathways that originate at the ER, we will pursue these specific aims: 1) Identify intra- and extra-genic factors
that control the subcellular itinerary and activity of Gyp8; 2) Determine target Rab GTPase(s) regulated by
Gyp8 in the secretory pathway; and 3) Define the role of Gyp8 in regulating peroxisomal and mitochondrial
dynamics. The proposed research is innovative both for area of focus and technical approach. While
Ypt1/Rab1 signaling controls multiple transport pathways essential to cellular health, understanding of where
and when signal must be terminated to accomplish each of its roles is particularly incomplete. The
experimental plan combines gold standard biochemical and imaging techniques in organelle and vesicular
transport (enzyme-coupled kinetic transport assays and 3D electron tomography) with systems biology
approaches (synthetic gene array and affinity capture mass spectrometry proteomics). The proposed research
is significant because defining how Ypt1/Rab1 is regulated to support and exercise quality control of ER,
mitochondria and peroxisomes is foundational to understanding aspects of cardiovascular, neurodegenerative
and metabolic disorders.

## Key facts

- **NIH application ID:** 10172761
- **Project number:** 1SC2GM140979-01
- **Recipient organization:** CALIFORNIA STATE UNIV SAN BERNARDINO
- **Principal Investigator:** Daniel P. Nickerson
- **Activity code:** SC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $142,590
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172761

## Citation

> US National Institutes of Health, RePORTER application 10172761, A transmembrane Rab GTPase accelerating protein targeted to peroxisomes (1SC2GM140979-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10172761. Licensed CC0.

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