# Molecular regulation of endosome fission during endocytic recycling

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2024 · $411,227

## Abstract

PROJECT SUMMARY:
Recycling endosomes, organelles intimately involved in the return of proteins and lipids to the plasma
membrane after their endocytosis, are of fundamental importance to plasma membrane turnover and the
control of plasma membrane composition. Advancing mechanistic understanding of recycling endosome
formation and function thus holds broad relevance to many areas of biomedicine. The mechanisms that
regulate recycling endosome biogenesis and function remain relatively poorly understood, lagging well behind
our understanding of other trafficking pathways. Our studies take advantage of the enormous technical
advantages in the simple animal model C. elegans that yield mechanistic insight into cell biological processes
within the physiologically relevant context of an intact metazoan animal. We then extend these find ings to
mammalian cells to expand understanding and define phylogenetic conservation. We focus on a system that
we pioneered, the C. e/egans intestine, a simple model that allows facile analysis of endocytic membrane
transport pathways within intact polarized epithelia. There is no cell division or cell replacement in the intestine
after embryogenesis, further simplifying analysis of mutant phenotypes. During the previous granting period we
greatly expanded our understanding of the essential endosomal regulator RME-8/DNAJC13. Our work
elucidated autoregulatory mechanisms controlling the RME-8 protein that allow RME-8 to regulate the
dynamics of endosomal coats and maintain separation of endosomal microdomains with conflicting functions.
We also showed that RME-8 is required for autophagic lysosome reformation in C. elegans and mouse
neurons, relevant to links between RME-8 to Parkinsonism. Our new studies during the last funding period also
focused our attention on fundamental forces that drive endosomal fission, particularly of recycling tubules that
must be severed from sorting endosomes to form recycling endosomes. Actin polymerization on endosomes
has long been proposed to provide necessary membrane tension to promote fission, but a clear understanding
of how actin contributes to tension, and how fission is regulated remain as large gaps in understanding that
require more in-depth study. Our studies provided surprising new evidence that non-muscle myosin II (NMII)
regulates endocytic recycling. We further discovered an endosomal signaling hub centered on the Syndapin
protein that controls endosomal RhoA and actomyosin. Here we propose extensive studies in C. elegans to
better define how the Syndapin pathway controls NMII and fission, extend this analysis into mammalian cells,
and determine the role of specific NMII isoforms in the fission process. We also identified a connection of
Syndapin-based RhoA-regulation that indicates signaling from endosomes to the nucleus for long-term
regulation of recycling. Our studies will test key predictions of these models and gain new understanding of
mechanisms that integrate acute ...

## Key facts

- **NIH application ID:** 10981032
- **Project number:** 2R01GM135326-05A1
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** Barth Demian Grant
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $411,227
- **Award type:** 2
- **Project period:** 2020-02-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981032

## Citation

> US National Institutes of Health, RePORTER application 10981032, Molecular regulation of endosome fission during endocytic recycling (2R01GM135326-05A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10981032. Licensed CC0.

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