# Mechanisms and function of endosome-derived tubular carriers

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $318,431

## Abstract

Endocytic trafficking is central to normal cell function, and dysregulation is the underlying cause for
diseases as diverse as atherosclerosis, diabetes and cancer. My laboratory has contributed to
understanding the mechanisms by which membranes and receptors are recycled via the endocytic
recycling compartment (ERC) to the plasma membrane (PM). Endocytic recycling remains one of the least
studied endocytic pathways; in particular, the involvement of membrane tubules in the recycling process is
poorly understood, and the roles of the various forms of tubular endosomes, and the mechanisms by which
these structures are generated and undergo vesiculation remain a major unanswered question. There are
multiple `types' of endosome-derived tubular carriers (EDTC), including sorting nexin-BAR (SNX-BAR)
domain and retromer-derived tubules, and networks of endosomal tubules, such as tubular recycling
endosomes (TRE) decorated by MICAL-L1, Syndapin2 (Synd2) and Eps15 Homology Domain (EHD)
proteins. Little is known about how these apparently different EDTC integrate their functions, or even
whether retromer and SXN-BAR EDTC are distinct from TRE. Recent studies demonstrate that EHD
proteins and MICAL-L1 interact with components of the retromer complex, suggesting that these tubular
networks are related. Our central hypothesis is that overlapping and distinct tubular membranes coordinate
transport from endosomes to the PM and the Golgi. In this proposal, we will uncover the functional and
physical relationships between TRE, retromer and SNX-BAR-derived EDTC. Moreover, we will focus on a
mechanistic understanding of the mode by which EDTC are generated, and how they undergo vesiculation
to promote transport within the cell. Aim 1: To examine the relationship and functional roles of EDTC.
Tubular endosomes play major roles in endocytic membrane trafficking. EDTC include a number of
retromer-containing structures, retromer-independent tubules generated by SNX-BAR domain proteins,
and TRE decorated by MICAL-L1, the BAR domain protein Synd2, and EHD proteins. We will examine the
cross-talk and cross-regulation of these pathways with regard to the generation and fission of recycling
tubules, and the control of endocytic recycling. Aim 2: To define and elucidate the spatio-temporal
regulation and mechanism of TRE biogenesis and vesiculation. Our working hypothesis is that
phosphatidic acid generation leads to recruitment of the membrane hub, MICAL-L1 and the F-BAR protein
Synd2, to generate and remodel TRE. We further hypothesize that EHD3 plays an essential role in this
process by stabilizing MICAL-L1-Synd2 interactions. Our studies on the cellular, organellar, molecular and
atomic levels will use techniques ranging from structural biology to super-resolution microscopy and novel
biophysical vesiculation assays, providing crucial knowledge of the functional role of the poorly understood
TRE and retromer-SNX-BAR derived tubules, and their biogenesis and vesiculation...

## Key facts

- **NIH application ID:** 10000963
- **Project number:** 5R01GM123557-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Steven H Caplan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $318,431
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000963

## Citation

> US National Institutes of Health, RePORTER application 10000963, Mechanisms and function of endosome-derived tubular carriers (5R01GM123557-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10000963. Licensed CC0.

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