Protective role of cytosolic prion protein against virus infection in prion-infected cells

• Published in: Journal of virology Vol. 98; no. 9; p. e0126224
• Main Authors: Hara, Hideyuki, Chida, Junji, Batchuluun, Batzaya, Takahashi, Etsuhisa, Kido, Hiroshi, Sakaguchi, Suehiro
• Format: Journal Article
• Language: English
• Published: United States 17-09-2024
• Subjects: Animals; Cell Line; Cytosol - metabolism; Humans; Inflammasomes - metabolism; Mice; Mitochondria - metabolism; Necroptosis; NF-kappa B - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Prion Diseases - metabolism; Prion Diseases - pathology; Prion Proteins - metabolism; Prions - metabolism; PrPSc Proteins - metabolism; Reactive Oxygen Species - metabolism; Superoxide Dismutase - metabolism; NF-κB; prion; NLRP3 inflammasome; influenza A virus; necroptosis; prion protein
• ISSN: 1098-5514
• DOI: 10.1128/jvi.01262-24

Production of the amyloidogenic prion protein, PrP
, which forms infectious protein aggregates, or prions, is a key pathogenic event in prion diseases. Functional prion-like protein aggregations, such as the mitochondrial adaptor protein MAVS and the inflammasome component protein ASC, have been identified to play a protective role in viral infections in mammalian cells. In this study, to investigate if PrP
could play a functional role against external stimuli, we infected prion-infected cells with a neurotropic influenza A virus strain, IAV/WSN. We found that prion-infected cells were highly resistant to IAV/WSN infection. In these cells, NF-κB nuclear translocation was disturbed; therefore, mitochondrial superoxide dismutase (mtSOD) expression was suppressed, and mitochondrial reactive oxygen species (mtROS) was increased. The elevated mtROS subsequently activated NLRP3 inflammasomes, leading to the suppression of IAV/WSN-induced necroptosis. We also found that prion-infected cells accumulated a portion of PrP molecules in the cytosol, and that the N-terminal potential nuclear translocation signal of PrP impeded NF-κB nuclear translocation. These results suggest that PrP
might play a functional role in protection against viral infections by stimulating the NLRP3 inflammasome-dependent antivirus mechanism through the cytosolic PrP-mediated disturbance of NF-κB nuclear translocation, which leads to suppression of mtSOD expression and consequently upregulation of the NLRP3 inflammasome activator mtROS.
Cytosolic PrP has been detected in prion-infected cells and suggested to be involved in the neurotoxicity of prions. Here, we also detected cytosolic PrP in prion-infected cells. We further found that the nuclear translocation of NF-κB was disturbed in prion-infected cells and that the N-terminal potential nuclear translocation signal of PrP expressed in the cytosol disturbed the nuclear translocation of NF-κB. Thus, the N-terminal nuclear translocation signal of cytosolic PrP might play a role in prion neurotoxicity. Prion-like protein aggregates in other protein misfolding disorders, including Alzheimer's disease were reported to play a protective role against various environmental stimuli. We here showed that prion-infected cells were partially resistant to IAV/WSN infection due to the cytosolic PrP-mediated disturbance of the nuclear translocation of NF-κB, which consequently activated NLRP3 inflammasomes after IAV/WSN infection. It is thus possible that prions could also play a protective role in viral infections.