ER protein SCAP inhibits Dengue virus NS2B3 protease by suppressing its K27-linked polyubiquitylation.

Abstract Dengue viruses (DENVs) are an emerging threat to global public health. The NS2B3 protease complex of DENV has recently been shown to cleave antiviral protein STING and thereby subverting the innate immune signaling to facilitate virus replication. Whether host cells have mechanism to counteract this virus-mediated immunosuppression is unclear. We discovered that the K27-linked poly-ubiquitination of NS3 protein facilitates its recruitment of NS2B and the formation of NS2B3, and consequently the enhanced cleavage of STING. However, an ER protein SCAP, through binding to NS2B protein, inhibits the ubiquitination of NS3, rendering NS2B3 protease incapable of binding and cleavage of STING. Importantly, ectopic-expression of SCAP impaired DENV infection, whereas silencing of SCAP potentiated DENV infection. Collectively, this study uncovered a novel function of SCAP to counteract the inhibitory action of DENV NS2B3 protease on the STING signaling, suggesting that modulation of SCAP levels may have therapeutic implications.IMPORTANCE This study reports the first ubiquitylation target protein in DENV: the NS3 protein and the unique role of the K27-linked poly ubiquitylation on NS3u0027 ability to recruit NS2B and formation of the NS2B3 protease complex. Additionally, this study identified novel functions of the ER protein SCAP: one is to compete with NS2B for binding to STING; another is to inhibit the ubiquitination of NS3. Both of these functions protect STING from being cleaved by the NS2B3 protease, and thus contribute to host antiviral response.