A study led by EPFL researchers reveals how a reversible fat-based modification controls a key protein involved in tissue health, a rare genetic disease, and anthrax toxin entry into cells.Every cell carefully builds and positions thousands of proteins that allow it to sense and respond to its surroundings. Even small changes to these proteins often determine whether they work properly or are destroyed before they ever reach the cell surface.One such protein is CMG2. By binding collagen VI, it helps maintain the extracellular matrix, the network of molecules that supports tissues throughout the body.CMG2 also serves as the main entry point for anthrax toxin produced by the bacterium that causes this potentially fatal infectious disease. Mutations that disrupt the protein cause Hyaline Fibromatosis Syndrome, a rare inherited disorder in which connective tissue builds up excessively, leading to painful and often life-threatening complications.But what is the molecular process that controls the life cycle of CMG2? This is exactly what Laurence Abrami and colleagues from the team led by Gisou van der Goot at EPFL have now uncovered. The study shows that CMG2 is regulated by repeated cycles of S-acylation, a chemical modification that occurs in a protein after it is synthesized and that consists of the reversible attachment and removal of fatty acid molecules (lipids). These cycles determine whether the protein folds correctly, reaches the cell surface, responds to external signals, or allows anthrax toxin to enter cells.From the laboratory to the cell membraneThe researchers tracked CMG2 from the moment it is produced inside the cell until it reaches the plasma membrane. They combined genetic approaches, biochemical experiments, high-resolution imaging, mouse studies, and experiments in zebrafish.They found that two enzymes first attach fatty acids, or lipids, to specific sites on newly made CMG2 inside the cell. This modification stabilizes the protein while it folds into its correct shape and protects it from being broken down by the cell's quality control system. Another enzyme then adds a third fatty acid, helping CMG2 travel from the Golgi apparatus to the cell surface.Once CMG2 reaches the cell membrane, the process reverses. When the protein binds collagen VI or anthrax toxin, another enzyme, APT2, removes the fatty acids. This allows CMG2 to detach from the cell's internal scaffolding and switch into a state that supports signaling and endocytosis, the process cells use to bring material inside.A block that has protective effects on cells and tissuesBlocking APT2 had striking effects. The researchers found that CMG2 remained protected during its production, increasing the amount of this protein available in cells and in mouse tissues. The same treatment also prevented efficient anthrax toxin entry. In cultured cells, toxin activity dropped sharply, and in zebrafish exposed to anthrax lethal toxin, inhibition of APT2 greatly reduced the vascular defects normally caused by the toxin.The findings suggest that carefully controlling APT2 activity might one day increase CMG2 levels in patients with Hyaline Fibromatosis Syndrome or help protect against anthrax infection by blocking the entry of the toxin into cells, pointing to new therapeutic possibilities. More broadly, the study suggests that similar lipid switches, capable of adding or removing fatty acids from proteins, may regulate many membrane proteins involved in human disease.Other contributorsEPFL Center of PhenoGenomicsUniversity of Geneva, SwitzerlandNanyang Technological University, SingaporeFundingSwiss National Science Foundation (SNSF)Gelù FoundationCARIGEST SAFondazione Teofilo Rossi di Montelera e di PremudaReferencesLaurence Abrami, Octave Joliot, Sanja Blaskovic, Guillaume Valentin, Covadonga Fernandez Hevia, Vincent Mercier, Béatrice Kunz, Francisco S. Mesquita, F. Gisou van der Goot. Dynamic S-acylation controls CMG2 maturation, extracellular matrix regulation, and anthrax toxin susceptibility in vivo. Nature Communications 06 July 2026. DOI: 10.1038/s41467-026-75028-2