Oligoadenylate synthetase 1a suppresses prion infection through binding to cellular prion protein.

Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein (PrPC) into its infectious β-sheet-rich isoform (PrPSc). Conventionally, prions were thought to be incapable of eliciting robust immune responses because PrPC and PrPSc share an identical primary structure. However, recent evidence highlights the critical involvement of type I interferon (I-IFN) signaling in host defense against prion propagation. Although we have previously shown that I-IFN, activated by interferon regulatory factor 3 (IRF3), plays an essential role in limiting prion invasion, the precise mechanisms underlying its protective effects remain unclear. Here, using in vivo and ex vivo prion infection models, we discovered that 2'-5' oligoadenylate synthetase 1a (Oas1a), an interferon-stimulated gene downstream of the I-IFN receptor, inhibits prion invasion at an early stage. Using Oas1a-knockout mice, we show that loss of Oas1a significantly accelerates prion disease progression and shortens survival, demonstrating its protective role in vivo. Consistent with this, mouse embryonic fibroblasts from Oas1a-knockout mice exhibited significantly increased susceptibility to 22L prion infection, effectively abrogating the anti-prion effects of I-IFN treatment. In addition, we found that recombinant Oas1a, when applied extracellularly, inhibited prion propagation without activating conventional RNase L pathways. Mechanistically, Oas1a directly binds PrPC, preventing its conversion to PrPSc and thus limiting PrPSc accumulation in vitro. These findings highlight the critical role of the IFN-Oas1a axis in limiting prion propagation and underscore its potential as a novel therapeutic target for prion diseases.