# Mechanisms of polarized protein sorting in AP-1B-deficient epithelia

> **NIH NIH R35** · WAYNE STATE UNIVERSITY · 2024 · $385,000

## Abstract

Project Summary
 Epithelial cells carry out secretory and absorptive functions that require the polarized distribution of
transporters, receptors and adhesion molecules at the apical and basolateral plasma membranes. Acquisition
and maintenance of apical-basolateral polarity involves sorting of plasma membrane proteins along the
biosynthetic and recycling pathways. The question of how apical and basolateral proteins in transit to the plasma
membrane are sorted in endosomal compartments has been at the center of research effort for decades. An
important mechanism of protein sorting is mediated by the clathrin adaptor protein AP-1B, which is a feature of
epithelial cells. AP-1B recognizes cargo at discrete sorting motifs and it was initially identified as mediator of
basolateral sorting. However, recent research by the applicant and others has determined that AP-1B also
mediates apical sorting. Moreover, some epithelia like the kidney proximal tubule and the retinal pigment
epithelium constitutively lack AP-1B. Therefore, additional mediators of polarized sorting must exist in these
epithelia. This fact, and our fluid understanding of AP-1B-mediated trafficking warrants revisions of the traditional
models of polarized protein sorting in epithelial cells. Filling these gaps in knowledge will reveal mechanisms
that can be exploited to understand and treat pathologies where epithelial physiology is compromised. The
applicant’s research program aims to characterize mechanisms of polarity in AP-1B-deficient epithelia and their
role in tissue organization, homeostasis and disease. The focus of the current R35 application will be on epithelial
cells of the kidney proximal tubule and retinal pigment epithelium, which lack AP-1B. We will study the roles of
an endosomal sorting protein previously characterized in non-polarized cells, sorting nexin-27 (SNX27) and
vesicle-associated membrane proteins (VAMPs) in polarized trafficking. We will also employ proteomics and
high throughput approaches to identify additional molecular mediators of polarized trafficking. We will test
whether the identified mechanisms mediate apical delivery of Megalin, a physiologically relevant surface receptor
expressed in kidney proximal tubule and retinal pigment epithelium. The R35 funding mechanism is an excellent
fit for achieving these goals, since it is intended to support the pursue of ambitious and flexible ideas with the
intent of developing the applicant’s research and training program, rather than an individual project. At the same
time, completing this proposal will lay out foundations for future advances in diagnosis, treatment, and prevention
of diseases, therefore directly contributing to the mission of the National Institute of General Medical Sciences.

## Key facts

- **NIH application ID:** 10894292
- **Project number:** 5R35GM150570-02
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Paulo Sebastian Caceres
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894292

## Citation

> US National Institutes of Health, RePORTER application 10894292, Mechanisms of polarized protein sorting in AP-1B-deficient epithelia (5R35GM150570-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10894292. Licensed CC0.

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