S-acylation in apoptotic and non-apoptotic cell death: a central regulator of membrane dynamics and protein function.

Abstract

Protein lipidation is a collection of important post-translational modifications that modulate protein localization and stability. Protein lipidation affects protein function by facilitating interactions with cellular membranes, changing the local environment of protein interactions. Among these modifications, S-acylation has emerged as a key regulator of various cellular processes, including different forms of cell death. In this mini-review, we highlight the role of S-acylation in apoptosis and its emerging contributions to necroptosis and pyroptosis. While traditionally associated with the incorporation of palmitic acid (palmitoylation), recent findings indicate that other fatty acids can also participate in S-acylation, expanding its functional repertoire. In apoptosis, S-acylation influences the localization and function of key regulators such as Bcl-2-associated X protein and other proteins modulating their role in mitochondrial permeabilization and death receptor signaling. Similarly, in necroptosis, S-acylation of mixed lineage kinase domain-like protein (MLKL) with palmitic acid and very long-chain fatty acids enhances membrane binding and membrane permeabilization, contributing to cell death and inflammatory responses. Recent studies also highlight the role of S-acylation in pyroptosis, where S-acylated gasdermin D facilitates membrane localization and pore assembly upon inflammasome activation. Blocking palmitoylation has shown to suppress pyroptosis and cytokine release, reducing inflammatory activity and tissue damage in septic models. Collectively, these findings underscore S-acylation as a shared and important regulatory mechanism across cell death pathways affecting membrane association of key signaling proteins and membrane dynamics, and offer insights into the spatial and temporal control of protein function.