The Emerging Role of Nuclear Viral DNA Sensors

Abstract

Detecting pathogenic DNA by intracellular receptors termed "sensors" is critical toward galvanizing host immune responses and eliminating microbial infections. Emerging evidence has challenged the dogma that sensing of viral DNA occurs exclusively in sub-cellular compartments normally devoid of cellular DNA. The interferon-inducible protein IFI16 was shown to bind nuclear viral DNA and initiate immune signaling, culminating in antiviral cytokine secretion. Here, we review the newly characterized nucleus-originating immune signaling pathways, their links to other crucial host defenses, and unique mechanisms by which viruses suppress their functions. We frame these findings in the context of human pathologies associated with nuclear replicating DNA viruses.Existing under the constant risk of invasion by pathogenic microorganisms, mammalian cells employ an array of constitutively expressed, germ-line-encoded receptors to survey the intra-and extracellular milieu for pathogen-or damage-associated molecules. Binding of these cellular receptors to their specific ligands evokes intracellular immune signaling cascades that culminate in the robust expression and secretion of antiviral cytokines, such as type I interferons (IFNs). Upon their release from the cell, these induced signaling factors operate in both an autocrine and a paracrine manner, inciting nearby cells to assume antiviral transcriptional programs. Cytokines further stimulate mammalian innate and adaptive immune responses, including the recruitment of antigen-presenting or cytotoxic leukocytes and the production of microbe-specific antibodies. Altogether, these cytokine-coordinated events promote the elimination of the invading pathogen. Thus, the molecular mechanisms mediating the recognition of and response to microbial molecular signatures are critically important.The DNA genomes of DNA viruses, a class of prevalent human pathogens, serve as one such immunogenic molecular signature. For preventing spurious auto-activation with cellular "self" DNA, the intracellular surveillance of viral DNA was thought to occur exclusively in cytosolic and endosomal compartments. However, this model fails to reconcile the fact that nearly all DNA viruses deposit and replicate their DNA genomes exclusively within host nuclei. As part of a shifting paradigm, recent studies have established the existence of cellular DNA sensors that detect viral DNA within the nucleus to trigger immune signaling. Here, we review the recent discoveries and ongoing challenges within the emerging field of nuclear DNA sensing.

Regulatory Interaction between the Cellular Restriction Factor IFI16 and Viral pp65 (pUL83) Modulates Viral Gene Expression and IFI16 Protein Stability

“…While the interference of retroviral replication by cellular RFs and retroviral evasion strategies have been studied in great detail, our knowledge of the mechanisms through which RFs affect other viral infections remains limited (3-5). In particular, in the case of HCMV at least two cellular components, namely, nuclear domain 10 (ND10) (e.g., promyelocytic leukemia protein [PML], hDaxx, and Sp100) and the interferon-␥-inducible protein 16 (IFI16), have emerged as critical restriction factors involved in mediating intrinsic immunity against this virus (6-9).The IFI16 protein, a member of the p200 family of proteins, now assigned to the PYHIN family (10)(11)(12)(13)(14), contains an N-terminal Pyrin domain and two partially conserved 200-aminoacid domains (HIN domains). In addition to sensing and binding foreign DNA (15-17), IFI16 displays multifaceted activity …”

“…The IFI16 protein, a member of the p200 family of proteins, now assigned to the PYHIN family (10)(11)(12)(13)(14), contains an N-terminal Pyrin domain and two partially conserved 200-aminoacid domains (HIN domains). In addition to sensing and binding foreign DNA (15-17), IFI16 displays multifaceted activity …”

“…The IFI16 protein, a member of the p200 family of proteins, now assigned to the PYHIN family (10)(11)(12)(13)(14), contains an N-terminal Pyrin domain and two partially conserved 200-aminoacid domains (HIN domains). In addition to sensing and binding foreign DNA (15)(16)(17), IFI16 displays multifaceted activity due to its ability to bind to various target proteins (including transcription factors, signaling proteins, and tumor suppressor proteins) and to modulate a multitude of various cell and viral functions (12,13,(18)(19)(20)(21)(22)(23).…”

“…In addition to sensing and binding foreign DNA (15)(16)(17), IFI16 displays multifaceted activity due to its ability to bind to various target proteins (including transcription factors, signaling proteins, and tumor suppressor proteins) and to modulate a multitude of various cell and viral functions (12,13,(18)(19)(20)(21)(22)(23). IFI16 has been shown to interact with the tegument protein pp65 of HCMV at the major immediate-early promoter/enhancer (MIEP) early during infection, resulting in the upregulation of IE protein expression (20).…”

Proteomics Tracing the Footsteps of Infectious Disease

“…At the onset of infection, the host cell relies on intracellular immune surveillance mechanisms, often through recognition of foreign nucleic acids by sensor proteins (48). Alternatively, binding of host proteins to foreign genomes may be propathogenic, recruited to their genomes to facilitate pathogen replication (49).…”