# Proteostasis and Phosphate Sensing in the Regulation of the Phosphate Transporter SLC20A1

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $410,000

## Abstract

PROJECT SUMMARY / ABSTRACT
The mechanisms by which mammalian cells sense phosphate availability to maintain homoestasis of this critical
nutrient are unknown. Phosphate is indispensable for many biological functions including DNA and RNA
synthesis, bone formation, and preservation of energy as high energy phosphates. Consequently, serious
complications develop during phosphate deficiency, e. g. rhabdomyolysis, and during phosphate excess, e. g.
cardiovascular disease and vascular calcification. Genetic mutations that lead to massive phosphate excess are
associated with a premature aging syndrome. A hallmark of vascular calcification is induction of the sodium-
coupled phosphate transporter SLC20A1/PiT1, and SLC20A1 is also induced in aggressive cancers. SLC20A1
is 1) widely expressed, 2) provides phosphate for basic cellular functions, and is 3) massively upregulated in
phosphate-starved cells. To interrogate the mechanisms underlying SLC20A1 regulation and more broadly
phosphate homeostasis and sensing, we performed a set of complementary CRISPR-based genome-wide loss-
of-function genetic screens in phosphate-replete and in phosphate-starved cultured mammalian cells. We found
that proteostasis plays a crucial role in the regulation of SLC20A1 protein abundance through regulation of
protein degradation, recycling, and synthesis. We hypothesize that phosphate starvation is detected by thus far
unidentified phosphate sensing machinery, which leads to coordinated regulation of SLC20A1 degradation,
recycling, and synthesis resulting in increased SLC20A1 protein abundance. We will examine this hypothesis
through three independent yet synergistic projects. In Project 1, we will examine the mechanisms governing
SLC20A1 internalization and degradation. Interestingly, loss of one of our candidate negative regulators of
SLC20A1 degradation leads to a premature aging syndrome that closely resembles genetic syndromes with
phosphate excess. Therefore, we will examine if decreased SLC20A1 internalization and degradation with
dysregulated cellular phosphate uptake also leads to a premature aging phenotype. In Project 2, we will examine
the mechanisms for SLC20A1 recycling to the plasma membrane, which will also be informative for many other
proteins as this process is generally not well understood. In Project 3, we will examine the role of protein
synthesis in the regulation of SLC20A1 protein abundance. Each Project is designed to also identify members
of the underlying phosphate sensing machinery. Our ultimate goal is identification of novel pharmacological
targets for the treatment of hypo- and hyperphosphatemic patients, which makes these studies highly clinically
relevant.

## Key facts

- **NIH application ID:** 10940492
- **Project number:** 1R35GM154877-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Peter Gerhard Christoph Zechner
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,000
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940492

## Citation

> US National Institutes of Health, RePORTER application 10940492, Proteostasis and Phosphate Sensing in the Regulation of the Phosphate Transporter SLC20A1 (1R35GM154877-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10940492. Licensed CC0.

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