# Lipidation as a post-translational code for protein liquid-liquid phase separation

## TL;DR

The paper explores how lipid modifications on proteins influence liquid-liquid phase separation, a process important for forming cellular compartments and regulating functions like gene expression.

## Contribution

The study introduces lipidation as a molecular code that regulates phase separation and condensate dynamics, extending the concept to include nuclear phosphoinositides like PI(4,5)P2.

## Key findings

- Lipidation modulates protein hydrophobicity and membrane affinity, influencing phase separation and condensate assembly.
- PI(4,5)P2 metabolism connects chromatin remodeling and transcriptional control through liquid-liquid phase separation.
- Covalent lipidations like palmitoylation and myristoylation regulate membrane organization and nuclear condensate architecture.

## Abstract

Liquid–liquid phase separation has emerged as a central organizing mechanism that drives the formation of biomolecular condensates and enables cells to spatially and temporally coordinate metabolism, signaling, and gene expression. While the influence of post-translational modifications such as phosphorylation and ubiquitination on condensate behavior is well-established, the contribution of lipidation, the covalent attachment of lipid moieties to proteins, to these processes has received far less attention. Lipidation dictates protein hydrophobicity, membrane affinity, and subcellular distribution, yet how these parameters influence LLPS and thereby modulate condensate dynamics remains unclear. We propose that lipidation operates as a molecular code that integrates membrane association with phase separation, thereby tuning the assembly, composition, and thus functional output of condensates. Extending this concept beyond classical membrane systems, we further suggest that nuclear phosphoinositides, particularly phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), may act as an unconventional lipid modifier that structures membraneless nuclear compartments through a process termed PIPoylation. Drawing on recent findings, we outline how canonical covalent lipidations, including palmitoylation, myristoylation, prenylation, and phospholipidation, govern membrane nanodomain organization, autophagy, and nuclear condensate architecture. We discuss how covalent lipidation influences condensate wetting, membrane curvature, and lipid–protein demixing, and how PI(4,5)P2 metabolism links chromatin remodeling with transcriptional control via LLPS. Together, these mechanisms underscore lipidation as a crucial regulator of condensate-membrane communication across cellular compartments.