The ERAD pathway mediates cross talk between two control points in cholesterol synthesis: HMG CoA reductase and...

Two key enzymes, HMG CoA reductase (HMGCR) and squalene monooxygenase (SM), are subjected to distinct endoplasmic reticulum-associated degradation (ERAD) pathways to maintain cholesterol homeostasis. HMGCR catalyzes conversion of HMG CoA to mevalonate, the first rate-limiting step in cholesterol synthesis. Sterols accelerate ERAD of HMGCR by promoting its binding to Insig proteins, which recruit E3 ubiquitin ligases for ubiquitination and degradation. Downstream, SM catalyzes oxygenation of squalene, committing intermediates to sterol synthesis. Cholesterol stimulates ERAD of SM, but through an Insig-independent mechanism mediated by the E3 ligase MARCH6. Here, we report a mechanism of posttranslational regulation involving a stable complex between HMGCR and SM in sterol-deprived cells. The two enzymes physically interact within ER membranes in an Insig-independent manner, and this interaction protects both proteins from ERAD. Loss of either enzyme destabilizes the other, indicating a costabilization mechanism. These findings uncover a layer of coordination in cholesterol synthesis, suggesting HMGCR and SM function as an integrated complex to ensure synchronization of early and late steps of the pathway.