Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection

Aguirre S, Luthra P, Sanchez-Aparicio MT, Maestre AM, Patel J, Lamothe F, Fredericks AC, Tripathi S, Zhu T, Pintado-Silva J, Webb LG, Bernal-Rubio D, Solovyov A, Greenbaum B, Simon V, Basler CF, Mulder LC, García-Sastre A, Fernandez-Sesma A1,3,5

.          Nat Microbiol. 2017 Mar 27;2:17037.

Speaker: Hsin-Hua Lu (盧信樺)                           Time: 1300~1400 May. 2, 2018

Commentator: Dr. Oscar Perng (彭貴春老師)   Place: Room 601

Abstract

Dengue virus (DENV) is a positive-sense RNA virus whose genome contains only one open reading frame encoding a large polypeptide. To obtain all functional viral proteins for replication, the DENV polypeptide is cleaved co- and/or post-translationally by either virus-encoded protease NS2B3 or by cellular proteases. Previous studies revealed a noncanonical function of DENV protease that antagonizes host type I interferon (IFN) system by cleaving stimulator of interferon genes (STING), a well-known adaptor in DNA sensing pathway (1). However, little is known about why DENV activates and manipulates this DNA sensing pathway. In this study, the authors showed that cyclic GMP-AMP synthase (cGAS), a DNA sensor catalyzes unconventional cyclic dinucleotides to activate STING, bound to mitochondrial DNA during DENV infection. In the absence of endogenous cGAS, IFN mRNA level was reduced, which then benefited DENV RNA replication and progeny production. Interestingly, a cGAS protein down-regulation phenomenon was accompanied with STING cleavage in DENV infected cells. To understand whether cGAS degradation was targeted by DENV protease complex, human cGAS and DENV NS2B3 were co-expressed in cell culture systems. In addition to the down-regulation of cGAS protein and detection of its degradation products, NS2B3 inhibited IFN-b induction irrespective of STING cleavage phenomenon. These data suggested that cGAS is also targeted by DENV NS2B3. Co-expression of cGAS with NS2B3 subunits, they found that NS2B alone, rather than NS3, is sufficient to degrade cGAS by host lysosomal system. Taken together, these data may explain why RNA virus infection is detected by DNA sensor and how DENV escaped from innate immune surveillance.

References:

1. Yu CY, et al. Dengue virus targets the adaptor protein MITA to subvert host innate immunity. PLoS Pathog. 2012;8(6):e1002780.