# PXA domain-containing proteins in lysosome function and lipid metabolism

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $405,000

## Abstract

PI: W. Mike Henne, Ph.D.
Project Summary/Abstract
 Lysosomes are the terminal organelle for major cellular catabolic pathways including
autophagy and endomembrane trafficking, yet remarkably little is understood about how they rid
themselves of the cellular debris they generate. Defects in this efflux contribute to nearly fifty
genetic diseases collectively known as lysosomal storage diseases (LSDs), and no universal
therapies are available for their treatment. Beyond their roles in catabolic metabolism,
lysosomes also supply basic metabolites like fatty acids (FAs) to other organelles of the cell, but
the mechanisms that govern this inter-organelle trafficking also remain obscure. I recently
characterized a family of proteins that potentially enable this inter-organelle lipid flux. All
homologs feature a poorly characterized PX-Associated (PXA), which preliminary data from my
lab indicates directly binds to FAs. I hypothesize that PXA domains contribute to non-vesicular
inter-organelle lipid exchange. Interestingly, I discovered that the yeast PXA domain-containing
protein Mdm1 functions as inter-organelle “tether” closely connecting the lysosome/vacuole to
the Endoplasmic Reticulum, the major lipid synthesis organelle. Mdm1's fly homolog—called
Snazurus (Snz)—is also implicated in lipid metabolism and aging, and snz-deficient flies exhibit
obesity and hyper-extended lifespan. The human homolog Snx14 was recently implicated in
pediatric neurological disease, likely caused by a newly recognized LSD.
 Collectively, I propose that PXA domain-containing proteins are important mediators of
inter-organelle lipid flux and metabolism, and may function to promote the movement of
metabolites like FAs between cellular organelles. These proteins thus constitute previously
unrecognized but important “hubs” of lipid metabolism and lysosome homeostasis. The research
program outlined here will define the functions of PXA domain-containing proteins in lysosome
function and lipid metabolism through three broad approaches: high-throughput genetic
screening, the reconstitution of inter-organelle tethering, and developing in organismo lipidomics
technologies. By implementing these approaches in my new lab, we will establish ourselves on
the leading edge of a paradigm-shifting era that will define new pathways and mechanisms of
non-vesicular lipid trafficking. These discoveries promise new therapies for LSDs, as well as
new therapeutic strategies for chronic metabolic syndromes like diabetes and heart disease.

## Key facts

- **NIH application ID:** 9994751
- **Project number:** 5R35GM119768-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Mike Henne
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994751

## Citation

> US National Institutes of Health, RePORTER application 9994751, PXA domain-containing proteins in lysosome function and lipid metabolism (5R35GM119768-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9994751. Licensed CC0.

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