# A genome-wide CRISPR screen identifies GRA38 as a key regulator of lipid homeostasis during Toxoplasma gondii adaptation to lipid-rich conditions

## TL;DR

A study finds that GRA38 helps the parasite Toxoplasma gondii manage lipids, which is crucial for its survival and virulence.

## Contribution

Identifies GRA38 as a novel lipid homeostasis regulator in Toxoplasma gondii using a CRISPR screen.

## Key findings

- GRA38 has phosphatidic acid phosphatase activity, essential for lipid homeostasis in Toxoplasma.
- Disruption of GRA38 causes lipid imbalances and reduced parasite virulence in mice.
- GRA38's activity is linked to adaptation to lipid-rich environments.

## Abstract

Intracellular parasites like Toxoplasma gondii scavenge host nutrients, particularly lipids, to support their growth and survival. Although Toxoplasma is known to adjust its metabolism based on nutrient availability, the mechanisms that mediate lipid sensing and metabolic adaptation remain poorly understood. Here, we performed a genome-wide CRISPR screen under lipid-rich (10% Fetal Bovine Serum (FBS)) and lipid-limited (1% FBS) conditions to identify genes critical for lipid-responsive fitness. We identified the Toxoplasma protein GRA38 as a lipid-dependent regulator of parasite fitness. GRA38 exhibits phosphatidic acid (PA) phosphatase (PAP) activity in vitro, which is significantly reduced by mutation of its conserved DxDxT/V catalytic motif. Disruption of GRA38 led to the accumulation of PA species and widespread alterations in lipid composition, consistent with impaired PAP activity. These lipid imbalances correlated with reduced parasite virulence in mice. Our findings identify GRA38 as a metabolic regulator important for maintaining lipid homeostasis and pathogenesis in Toxoplasma gondii.