Impaired cortical actin dynamics via lanosterol-dependent HMG-CoA reductase downregulation mediates IFN-α-induced...

Independent studies have reported that interferon-β induces CYP51A1 downregulation leading to lanosterol (LAN) accumulation; that LAN triggers HMG-CoA reductase (HMGCR) downregulation; and that statin-mediated HMGCR inhibition suppresses mast cell activation. Building on these findings, we investigated whether the known mast cell-stabilizing effect of IFN-α/β is driven by this LAN-induced HMGCR downregulation. In bone marrow-derived mast cells (BMMCs), interferon-α (IFN-α) indeed induced HMGCR downregulation via both ubiquitin-mediated protein degradation and transcriptional suppression, alongside CYP51A1 downregulation and LAN accumulation. Cotreatment with terbinafine, a squalene epoxidase inhibitor used to prevent LAN synthesis, restored HMGCR expression to control levels and resulted in full recovery of bone marrow-derived mast cell function. Cotreatment with specific intermediates of the mevalonate (MVA) pathway (i.e., mevalonolactone, farnesol, and geranylgeraniol) also counteracted the mast cell-stabilizing effect of IFN-α, without altering the HMGCR and CYP51A1 expression levels. These results indicate that attenuating the MVA pathway via LAN-induced HMGCR downregulation is directly responsible for the observed IFN-α-induced mast cell stabilization. Notably, IFN-α compromised the cortical actin dynamics necessary for high-affinity IgE receptor-induced LAT-PLC-γ1 signalosome assembly. These dynamics and signalosome assembly were also fully restored by cotreatment with terbinafine or the MVA pathway intermediates, as well as by the F-actin-destabilizing agent cytochalasin D. These findings were validated in vivo using a mouse model of passive cutaneous anaphylaxis and ex vivo mast cell degranulation assays. Together, our study reveals a previously unrecognized mechanism of immune regulation in which IFN-α stabilizes mast cells by impairing cortical actin dynamics through the CYP51A1-LAN-HMGCR axis.