Dynamic S-acylation controls CMG2 maturation extracellular matrix regulation and anthrax toxin susceptibility in vivo.

CMG2/ANTXR2 functions as a Collagen VI receptor required for extracellular matrix homeostasis and as the primary portal for anthrax toxin entry. Mutations in CMG2 cause Hyaline Fibromatosis Syndrome (HFS), a rare and often fatal genetic disorder characterized by excessive extracellular matrix accumulation, yet the molecular mechanisms regulating CMG2 function remain poorly understood. We show that CMG2 is controlled by ordered cycles of S-acylation and deacylation that regulate its folding, trafficking, and signalling competence. S-acylation by ZDHHC7 on two juxtamembrane cysteines protects CMG2 from ER-associated degradation by stabilizing folding intermediates, leading to a ~ 5-fold increase in folded receptors competent for ER exit. In the Golgi, ZDHHC3-dependent acylation of a third cysteine promotes Arf6-mediated CMG2 transport to the plasma membrane, where it exerts its functions. Ligand binding triggers recruitment of the thioesterase APT2, which enables release of CMG2 from the actin cytoskeleton and endocytosis, linking extracellular recognition to intracellular signalling and uptake. Inhibition of APT2 reduces Collagen VI turnover and strongly attenuates anthrax toxin toxicity in a zebrafish model, showing lipidation cycles as regulators of receptor function and potential therapeutic targets.