{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:14:59Z","timestamp":1789647299152,"version":"4.0.0"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Breeding Plan of Shandong Provincial Technology-based SMEs Innovation Cabalibity Enhancement Project","award":["2025TSGCCZZB0064"],"award-info":[{"award-number":["2025TSGCCZZB0064"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32072818"],"award-info":[{"award-number":["32072818"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31772708"],"award-info":[{"award-number":["31772708"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2026,5,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Porcine reproductive and respiratory syndrome (PRRS) is a major economic burden to the global swine industry. Here, we identify the endoplasmic reticulum (ER) translocon component SSR4 as a critical host factor co-opted by PRRSV. We demonstrate that the viral non-structural protein Nsp2 physically interacts with SSR4 via its PLP2 and hypervariable domains and selectively upregulates its expression during infection by prolonging its protein half-life. Functional studies revealed that SSR4 is a proviral factor essential for efficient PRRSV replication. Mechanistically, SSR4 is required for the full activation of the PRRSV-induced ER stress response, specifically modulating the PERK-eIF2\u03b1 and IRE1\u03b1-XBP1 axes of the unfolded protein response. Notably, Nsp2 itself acts as a key inducer of ER stress and mediates the upregulation of SSR4, suggesting a potential feed-forward loop that sustains a virus-favorable ER environment. This relationship is finely balanced, as pharmacological disruption of ER homeostasis using either the inducer tunicamycin (TU) or the chemical chaperone 4-phenylbutyric acid (4-PBA) potently inhibited viral replication. Importantly, TU and another inducer, dithiothreitol, exhibited potent, broad-spectrum antiviral activity against multiple PRRSV genotypes in both cell lines and primary porcine alveolar macrophages. Our study delineates a novel pathogenesis model where PRRSV Nsp2 hijacks SSR4 to engineer a proviral ER stress niche. The Nsp2-SSR4-ER stress axis represents a promising target for the development of broad-spectrum antiviral strategies against PRRS.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>This study provides significant insights into porcine reproductive and respiratory syndrome virus (PRRSV) pathogenesis by identifying a novel and specific virus-host interface. We demonstrate that PRRSV, through its Nsp2 protein, hijacks a specific component of the host endoplasmic reticulum (ER) translocon SSR4 to orchestrate a tailored ER stress response conducive to viral replication. This mechanism is distinct from a general disruption of the TRAP complex, highlighting a precise viral strategy. Furthermore, the finding that pharmacological agents, which dysregulate this hijacked pathway\u2014particularly ER stress inducers\u2014act as potent, broad-spectrum antivirals challenges the conventional view of ER stress as a uniformly host-protective response. Our work not only uncovers a key molecular determinant of PRRSV replication but also validates the Nsp2-SSR4-ER stress axis as a promising and novel target for the development of much-needed, broad-spectrum therapeutic interventions against this economically devastating swine pathogen.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00266-26","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T12:36:12Z","timestamp":1776947772000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["The host protein SSR4 mediates PRRSV-induced endoplasmic reticulum stress via interaction with 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