探討p62/sequestosome-1蛋白促進登革病毒複製的角色

Abstract

Dengue is a re-emerging disease which is endemic in more than 100 countries throughout Africa, South-East Asia, America, and the Western Pacific. Due to global warming effects, the dengue virus (DV) threat is broadening in the world. The symptoms are febrile illness called dengue fever to dengue hemorrhagic fever and dengue shock syndrome. Autophagy, a cellular catabolic system responsible for damaged organelles and misfolded proteins degradation, is reported to facilitate DV replication. A recent study showed that sindbis virus is associated with an autophagy adaptor protein p62 that leads to elimination of virus by autophagy. However, our data here indicate that p62 seems to be required for DV replication. Compared to WT MEF cells, less virus proteins, released DV particles and DV RNA were detected in DV-infected p62-deficient MEF cells. Significant decreased DV protein translation was also observed in p62 knockdown DV-replicon stable expressing cells. This facilitating role of p62 to DV replication is not limited in MEF cells but also in hepatocyes and monocytes. There were no differences in virus cell binding, endocytosis, interferon activation and autophagy induction between DV-infected WT and p62-deficient cells. Lipid accumulation by p62 deficiency also showed no contribution to DV replication. However, DV triggered high NF-κB phosphorylation and nuclear translocation in p62-deficient cells. The reduced DV replication can be rescued by inactivation of NF-κB with inhibitor BAY 11-7082 in p62-deficient cells. Moreover, we found that NF-κB responsible cytokine IL-6 was highly produced in DV-infected p62-deficient cells. The co-localization of p62 with DV prM, E, NS2A and NS3 proteins from confocal microscopy observation indicates that p62 might interact with DV proteins to facilitate virus replication. Our findings uncover a new role of p62 in facilitating DV replication and also provide a potential therapeutic target for dengue infection.