Περίληψη:
Flaviviral infections including dengue virus are an increasing clinical
problem worldwide. Dengue infection triggers host production of the type
1 IFN, IFN alpha, one of the strongest and broadest acting antivirals
known. However, dengue virus subverts host IFN signaling at early steps
of IFN signal transduction. This subversion allows unbridled viral
replication which subsequently triggers ongoing production of IFN which,
again, is subverted. Identification of downstream IFN antiviral
effectors will provide targets which could be activated to restore broad
acting antiviral activity, stopping the signal to produce endogenous IFN
at toxic levels. To this end, we performed a targeted functional genomic
screen for IFN antiviral effector genes (IEGs), identifying 56 IEGs
required for antiviral effects of IFN against fully infectious dengue
virus. Dengue IEGs were enriched for genes encoding nuclear receptor
interacting proteins, including HELZ2, MAP2K4, SLC27A2, HSP90AA1, and
HSP90AB1. We focused on HELZ2 (Helicase With Zinc Finger 2), an IFN
stimulated gene and IEG which encodes a promiscuous nuclear factor
coactivator that exists in two isoforms. The two unique HELZ2 isoforms
are both IFN responsive, contain ISRE elements, and gene products
increase in the nucleus upon IFN stimulation. Chromatin
immunoprecipitation-sequencing revealed that the HELZ2 complex interacts
with triglyceride-regulator LMF1. Mass spectrometry revealed that HELZ2
knockdown cells are depleted of triglyceride subsets. We thus sought to
determine whether HELZ2 interacts with a nuclear receptor known to
regulate immune response and lipid metabolism, AHR, and identified
HELZ2: AHR interactions via co-immunoprecipitation, found that AHR is a
dengue IEG, and that an AHR ligand, FICZ, exhibits anti-dengue activity.
Primary bone marrow derived macrophages from HELZ2 knockout mice,
compared to wild type controls, exhibit enhanced dengue infectivity.
Overall, these findings reveal that IFN antiviral response is mediated
by HELZ2 transcriptional upregulation, enrichment of HELZ2 protein
levels in the nucleus, and activation of a transcriptional program that
appears to modulate intracellular lipid state. IEGs identified in this
study may serve as both (1) potential targets for host directed
antiviral design, downstream of the common flaviviral subversion point,
as well as (2) possible biomarkers, whose variation, natural, or
iatrogenic, could affect host response to viral infections.
Συγγραφείς:
Fusco, Dahlene N.
Pratt, Henry
Kandilas, Stephen
Cheon,
Scarlett Se Yun
Lin, Wenyu
Cronkite, D. Alex
Basavappa,
Megha
Jeffrey, Kate L.
Anselmo, Anthony
Sadreyev, Ruslan and
Yapp, Clarence
Shi, Xu
O'Sullivan, John F.
Gerszten, Robert
E.
Tomaru, Takuya
Yoshino, Satoshi
Satoh, Tetsurou and
Chung, Raymond T.
