# Regulation of Calcium Signaling by Protein Lipidation

> **NIH NIH R01** · ROWAN UNIVERSITY · 2022 · $332,739

## Abstract

ABSTRACT
Intracellular calcium signals play a vital role in regulating immune system homeostasis and function. In T cells,
calcium ions serve as a critical second messenger in a broad variety of cellular processes regulating T cell
activation, proliferation and differentiation of naïve T cells into effector or memory cells. The mechanism
supporting the sustained calcium influx into the cytoplasm is known as store-operated calcium entry (SOCE).
Two proteins, Orai1 and STIM1, were identified as primary modulators of SOCE in T cells. SOCE is initiated
when STIM1 senses the depletion of internal calcium stores and associates with the pore-forming Orai1 to
assemble the calcium release-activated channel. The critical role of STIM1 and Orai1 in the regulation of T cell
immune responses is well supported by genetic studies performed in animals as well as clinical data. Biological
consequences of Orai1 or STIM1 deficiencies include severe immunodeficiency, tubular aggregate myopathy,
and Stormorken syndrome. In our preliminary experiments, we have identified both Orai1 and STIM1 as
endogenously S-acylated proteins. S-acylation, a reversible post-translational lipidation of cysteine residues
with long-chain fatty acids, is catalyzed by the family of DHHC palmitoyl acyltransferases known to regulate the
function of many key T cell signaling proteins. Our previous studies strongly suggest that stimulus-dependent
protein lipidation is an essential part of the intricate signaling machinery controlling T cell activation and
function. Therefore, we hypothesize that dynamic S-acylation of Orai1 and STIM1 is a critical regulator
of calcium entry in T cells. To uncover the role of protein lipidation in calcium signaling, we will (1) determine
whether Orai1 and STIM1 are S-acylated proteins in T cells, (2) determine the functional consequences of
Orai1 and STIM1 acylation and (3) identify the enzymatic mechanisms mediating Orai1 and STIM1 S-acylation.
The successful completion of the proposed project will demonstrate the biological significance of protein
lipidation in regulation of SOCE as well as the role of palmitoyl acyltransferases in regulation of the calcium
signaling in T cells with relevance to primary immunodeficiency disease.

## Key facts

- **NIH application ID:** 10404120
- **Project number:** 5R01GM130840-04
- **Recipient organization:** ROWAN UNIVERSITY
- **Principal Investigator:** Askar Akimzhanov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $332,739
- **Award type:** 5
- **Project period:** 2019-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404120

## Citation

> US National Institutes of Health, RePORTER application 10404120, Regulation of Calcium Signaling by Protein Lipidation (5R01GM130840-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10404120. Licensed CC0.

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