ArticleThe Journal of biological chemistry2026
Impaired cortical actin dynamics via lanosterol-dependent HMG-CoA reductase downregulation mediates IFN-α-induced mast cell stabilization.
Article in The Journal of biological chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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