PRRSV N protein antagonizes host antiviral immune responses by upregulating HSPA1B to induce autophagic degradation of Fos-related antigen 1

[摘要] ABSTRACTPorcine reproductive and respiratory syndrome virus (PRRSV) infection often causes severe immunosuppression in pigs. However, the mechanisms by which PRRSV antagonizes host antiviral immune responses remain incompletely understood. We found that granulocyte-macrophage colony-stimulating factor (CSF2) was significantly upregulated in porcine alveolar macrophages (PAMs) upon PRRSV infection. CSF2 upregulation inhibits PRRSV replication by promoting IL15 expression, and Fos-related antigen 1 (FRA1) enhances the antiviral activity of the CSF2-IL15 axis via transcriptional regulation. Further investigation revealed that the PRRSV N protein directly interacts with HSPA1B and activates HSPA1B-mediated chaperone-mediated autophagy (CMA) to degrade FRA1, thereby antagonizing host antiviral immunity. Our study reveals that the PRRSV N protein promotes FRA1 autophagic degradation by upregulating heat shock protein HSPA1B, thereby suppressing the host CSF2-IL15 antiviral pathway. This study provides new insights into the arms race between PRRSV and the host, as well as novel perspectives for the development of anti-PRRSV infection strategies.IMPORTANCEFocusing on the core scientific issue of PRRSV immune evasion, this study identifies a novel pathway by which host FRA1 restricts viral infection through regulating the CSF2-IL15 cytokine axis. It reveals that the PRRSV N protein hijacks HSPA1B-mediated chaperone-mediated autophagy to target and degrade the transcription factor FRA1, thereby dismantling the host CSF2-IL15 antiviral defense and advancing the understanding of PRRSV-related immunosuppression. These findings elucidate a new paradigm in the host-pathogen tug-of-war, whereby viruses exploit autophagy machinery to eliminate critical immune regulators. This work also provides mechanistic insights for the development of intervention strategies targeting CMA and cytokine homeostasis.

[发布日期] 2026-09-09

[关键词] PRRSV;CSF2;FRA1;HSPA1B;chaperone-mediated autophagy