# Defining the Function of RME-8 in Endosomal Regulation During Health and Disease

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2020 · $383,917

## Abstract

Our long-term goal in this proposal is to understand how endosomes differentially
balance opposing activities (recycling versus degradation) within a single endosome,
especially with respect to regulation by the only known endosomal DNA-J domain
protein RME-8. We also seek to understand how RME-8 contributes to
neurodegenerative disease. To gain new insights into the mechanisms that balance
opposing endosomal functions, we have pioneered the use of the coelomocyte cells of
the nematode C. elegans for the direct visualization of endosomal microdomains, and
then applied powerful molecular genetic techniques to identify and decipher metazoan-
specific mechanisms that control endosome function and functional microdomain
separation. We then extend this work into mammalian systems. In previous studies, we
identified the J-domain protein RME-8 as a metazoan specific endosome regulator. We
further showed that RME-8 functions with Retromer component SNX-1/Snx1, and the
chaperone Hsc70, to promote the recycling of retromer cargo in C. elegans and
mammals. Most recently, we showed that RME-8 allows Retromer to negatively regulate
ESCRT assembly on endosomes, a process required to prevent mixing of recycling and
degradative microdomains. Here we propose to define how SNX-1 regulates RME-8,
testing a de-repression model for RME-8 activation. We then focus on mechanistic
questions of how RME-8 inhibits ESCRT microdomain expansion through the
endosomal flat clathrin lattice and newly identified RME-8 interacting proteins. Finally,
we use primary mouse neurons and in vivo C. elegans analysis to decipher neuronal
functions of RME-8 as revealed by analysis of a familial Parkinson’s associated allele of
RME-8. We propose to define how the disease allele affects RME-8 function in
endosomal recycling and microdomain maintenance, and determine how RME-8
regulates long-distance axonal transport of endosomes, an additional transport step in
neurons required for endocytic cargo sorting. A better mechanistic understanding of
these regulatory mechanisms of endosomes will be profoundly important in identifying
therapeutic targets to combat diseases associated with endolysosomal dysfunction.

## Key facts

- **NIH application ID:** 9862085
- **Project number:** 1R01GM135326-01
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** Qian Cai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,917
- **Award type:** 1
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9862085

## Citation

> US National Institutes of Health, RePORTER application 9862085, Defining the Function of RME-8 in Endosomal Regulation During Health and Disease (1R01GM135326-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9862085. Licensed CC0.

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