ARCN1 suppresses innate immune responses against respiratory syncytial virus by promoting STUB1-mediated IKKε degradation.

Respiratory syncytial virus (RSV), a filamentous, enveloped, negative-sense, single-stranded RNA virus, is a common cause of respiratory infections in pediatric and elderly populations, often leading to severe inflammation and lung damage. To date, there is no effective treatment for RSV infection. Therefore, elucidating the antiviral mechanism in RSV infection is critical for identifying potential effective therapeutic targets. Type I interferons (IFN-Is), especially IFN-β, play a key role in the immediate immune response against viral infection by inhibiting viral load and spread. Current studies have shown that ARCN1 (archain 1), the δ subunit of the coat protein complex I complex, is involved in intra-Golgi trafficking and protein transport from the Golgi apparatus back to the endoplasmic reticulum. In this study, we demonstrate that ARCN1 suppresses the anti-RSV innate immune response by promoting E3 ubiquitin ligase STUB1-mediated K48-linked polyubiquitination and subsequent proteasomal degradation of IKKε. Mechanistically, ARCN1 recognizes and binds to the δL motif of STUB1 via its flexible MHD domain while interacting with IKKε. This finding provides a theoretical basis for the development of new antiviral treatment strategies targeting ARCN1.