Silencing of ubiquitin specific protease-15 activates components of innate immune response and inhibits dengue virus infection.

Innate immune responses induced by interferons are one of the key defense mechanisms against virus infections. It is activated by specific sensors in host cells that detect particular features of viruses. Secretion of interferons stimulate interferon-stimulated genes (ISGs) that act as antiviral effectors and inhibit virus infections. Many factors, including post-translational modifications (PTMs) of host cell proteins modulate virus infections. Ubiquitination/deubiquitination is one such PTM that utilizes ligases and deubiquitinases, which viruses exploit to enhance their replication and evade immune responses. Ubiquitin-specific proteases (USPs), a group of deubiquitinases, play a major role in virus transmission by modulating the replication and propagation of viruses. In this study, we examined the role of USP-15 during Dengue virus (DENV) infection. Our results showed that USP-15 plays a crucial role in facilitating DENV replication. Knockdown of USP-15 using specific siRNAs abrogated replication of DENV in A549 cells. This was evidenced by decreased expression of DENV-NS1 and envelope protein in A549 cells silenced with USP-15. Furthermore, higher expression of MDA-5, IFN-β, and ISG-15, sensors of innate immune receptors, was noted in USP-15-silenced DENV infected cells, indicating the association of antiviral genes with USP-15. Therefore, USP-15 could be utilized as an effective target for combating DENV infection.