Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila

Abstract

In response to infection, the innate immune system rapidly activates an elaborate and tightly orchestrated gene expression program to induce critical antimicrobial genes. While many key players in this program have been identified in disparate biological systems, it is clear that there are additional uncharacterized mechanisms at play. Our previous studies revealed that a rapidly-induced antiviral gene expression program is active against disparate human arthropod-borne viruses in Drosophila. Moreover, one-half of this program is regulated at the level of transcriptional pausing. Here we found that Nup98, a virus-induced gene, was antiviral against a panel of viruses both in cells and adult flies since its depletion significantly enhanced viral infection. Mechanistically, we found that Nup98 promotes antiviral gene expression in Drosophila at the level of transcription. Expression profiling revealed that the virus-induced activation of 36 genes was abrogated upon loss of Nup98; and we found that a subset of these Nup98-dependent genes were antiviral. These Nup98-dependent virus-induced genes are Cdk9-dependent and translation-independent suggesting that these are rapidly induced primary response genes. Biochemically, we demonstrate that Nup98 is directly bound to the promoters of virus-induced genes, and that it promotes occupancy of the initiating form of RNA polymerase II at these promoters, which are rapidly induced on viral infection to restrict human arboviruses in insects.innate immunity | nuclear pore | nucleoporin | pol II regulation | P-TEFb

Selective Removal of FG Repeat Domains from the Nuclear Pore Complex by Enterovirus 2A pro

“…Work in Drosophila melanogaster has shown that, in addition to its role at the NPC, Nup98 also has a role in transcriptional induction during normal fly development and in the heat shock response (75,76). More recently, Panda et al showed that Nup98 is required for an effective antiviral transcription response in D. melanogaster (77). Combined with earlier work showing that Nup98 is itself induced by type I and II interferons, these results suggest the possibility that Nup98 may contribute to the antiviral response in mammals.…”

Innate and intrinsic antiviral immunity in Drosophila

“…For example, the cytokines Upd2 and Upd3, which activate the Jak/STAT pathway, are induced by DCV infection [35]. The nucleoporin Nup98, which is upregulated by SINV and VSV, participates in the induced expression of a subset of putative antiviral genes, together with the transcription factor FoxK [97, 98]. The gene Vago encodes a 18kDa Cystein-rich peptide containing a single von Willebrand factor type C domain, which probably represents another cytokine, participating in the amplification of the immune response [86].…”

Nuclear pore complexes and regulation of gene expression

“…NPC-associated Nup98, on the other hand, was described to bind a small subset of predominantly non-active genes [49]. Recently, Nup98 was also found to bind and regulate the expression of genes critical for the anti-viral response in Drosophila, but whether this association takes place inside the nucleus or at the nuclear periphery has not been investigated [50]. Other nucleoporins that were also found to bind active genes inside the nucleus include Nup50, Nup62, Sec13 and Nup153 [48,49,51] (Figure 2).…”