Dynamic S-acylation controls CMG2 maturation, extracellular matrix regulation, and anthrax toxin entry

ABSTRACT CMG2/ANTXR2 functions as a Collagen VI receptor and the primary portal for anthrax toxin entry. We find that CMG2 is regulated by ordered cycles of S-acylation and deacylation throughout its life cycle. Following synthesis in the endoplasmic reticulum, acylation by ZDHHC7 on two juxtamembrane cysteines protects folding intermediates from ER-associated degradation, resulting in a 5-fold increase in CMG2 biogenesis. The cytosolic thioesterase APT2 can remove these acyl chains, thereby controlling CMG2 levels. In the Golgi, CMG2 acylation by ZDHHC3 on a third cysteine to permit Arf6-dependent transport to the plasma membrane. At the cell surface, S-acylated CMG2 recruits APT2 in response to ligand binding, enabling release from the actin cytoskeleton and endocytosis. Accordingly, blocking APT2 suppresses the intracellular delivery of anthrax toxin, and inhibits CMG2-dependent Collagen VI degradation. These results define S-acylation–deacylation cycles as key regulators of CMG2 biogenesis and function, and highlight APT2 inhibition as a strategy to modulate CMG2 levels or prevent anthrax intoxication.