Interrogating Host Antiviral Environments Driven by Nuclear DNA Sensing: A Multiomic Perspective

Abstract

Nuclear DNA sensors are critical components of the mammalian innate immune system, recognizing the presence of pathogens and initiating immune signaling. These proteins act in the nuclei of infected cells by binding to foreign DNA, such as the viral genomes of nuclear-replicating DNA viruses herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). Upon binding to pathogenic DNA, the nuclear DNA sensors were shown to initiate antiviral cytokines, as well as to suppress viral gene expression. These host defense responses involve complex signaling processes that, through protein–protein interactions (PPIs) and post-translational modifications (PTMs), drive extensive remodeling of the cellular transcriptome, proteome, and secretome to generate an antiviral environment. As such, a holistic understanding of these changes is required to understand the mechanisms through which nuclear DNA sensors act. The advent of omics techniques has revolutionized the speed and scale at which biological research is conducted and has been used to make great strides in uncovering the molecular underpinnings of DNA sensing. Here, we review the contribution of proteomics approaches to characterizing nuclear DNA sensors via the discovery of functional PPIs and PTMs, as well as proteome and secretome changes that define a host antiviral environment. We also highlight the value of and future need for integrative multiomic efforts to gain a systems-level understanding of DNA sensors and their influence on epigenetic and transcriptomic alterations during infection.

Systematic profiling of protein complex dynamics reveals DNA-PK phosphorylation of IFI16 en route to herpesvirus immunity

“…Virus modulation of the host microenvironment begins at the moment of its cellular attachment and is evident at every stage of infection thereafter, including for immune evasion, metabolic reprogramming to accommodate viral genome synthesis, and alteration of trafficking pathways for egress ( 2 , 16 , 17 ). The ancient evolutionary history of Herpesviridae, coupled with their large coding capacity, has produced a family of viruses that all exert precise control over the infected host cell, but each with a distinct modality of replication.…”

“…For example, early during HSV-1 infection, the tegument protein pUL41 inhibits host transcription and translation to block immune responses that are triggered during capsid trafficking (13). The HSV-1 pUL37 and HCMV pUL31 proteins, among others, interact directly with the cytosolic DNA cyclic GMP-AMP synthase (cGAS) to inhibit its immune functions (14)(15)(16).…”

The DNA Sensor IFIX Drives Proteome Alterations To Mobilize Nuclear and Cytoplasmic Antiviral Responses, with Its Acetylation Acting as a Localization Toggle

“…5C ), we reasoned that acetylation might also contribute to cytoplasmic localization of IFIX. However, although different types of posttranslational modifications (PTMs) have been identified for IFI16 and other nuclear and cytoplasmic DNA sensors ( 35 ), no PTMs have been reported for IFIX in any biological context. Therefore, to determine whether IFIX is posttranslationally modified, we enriched IFIX-mGFP by immunoaffinity purification (IP) and performed mass spectrometry analyses.…”

Integrative systems biology characterizes immune-mediated neurodevelopmental changes in murine Zika virus microcephaly

“… 10 Such multi-omics approaches have recently been adopted to study immune ontogeny, the immune response to infectious diseases, and microbiomes. 11 , 12 , 13 , 14 …”