Article

Identification and characterization of a loss-of-function human MPYS variant.

Integrated Department of Immunology, University of Colorado Denver School of Medicine and National Jewish Health, Denver, CO 80206-2762, USA.
Genes and immunity (Impact Factor: 4.22). 01/2011; 12(4):263-9. DOI: 10.1038/gene.2010.75
Source: PubMed

ABSTRACT MPYS, also known as STING and MITA, is an interferon (IFN)β stimulator essential for host defense against RNA, DNA viruses and intracellular bacteria. MPYS also facilitates the adjuvant activity of DNA vaccines. Here, we report identification of a distinct human MPYS haplotype that contains three non-synonymous single nucleotide polymorphisms (SNPs), R71H-G230A-R293Q (thus, named the HAQ haplotype). We estimate, in two cohorts (1,074 individuals), that ∼3% of Americans are homozygous for this HAQ haplotype. HAQ MPYS exhibits a > 90% loss in the ability to stimulate IFNβ production. Furthermore, fibroblasts and macrophage cells expressing HAQ are defective in Listeria monocytogenes infection-induced IFNβ production. Lastly, we find that the loss of IFNβ activity is due primarily to the R71H and R293Q SNPs in HAQ. We hypothesize that individuals carrying HAQ may exhibit heightened susceptibility to viral infection and respond poorly to DNA vaccines.

0 Bookmarks
 · 
99 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: A principal barrier to the development of effective vaccines is the availability of adjuvants and formulations that can elicit both effector and long-lived memory CD4 and CD8 T cells. Cellular immunity is the presumptive immune correlate of protection against intracellular pathogens: a group composed of bacteria, viruses and protozoans that is responsible for a staggering level of morbidity and mortality on a global scale. T-cell immunity is also correlated with clinical benefit in cancer, and the development of therapeutic strategies to harness the immune system to treat diverse malignancies is currently undergoing a renaissance. Cyclic dinucleotides (CDNs) are ubiquitous small molecule second messengers synthesized by bacteria that regulate diverse processes and are a relatively new class of adjuvants that have been shown to increase vaccine potency. CDNs activate innate immunity by directly binding the endoplasmic reticulum-resident receptor STING (stimulator of interferon genes), activating a signaling pathway that induces the expression of interferon-β (IFN-β) and also nuclear factor-κB (NF-κB) dependent inflammatory cytokines. The STING signaling pathway has emerged as a central Toll-like receptor (TLR) independent mediator of host innate defense in response to sensing cytosolic nucleic acids, either through direct binding of CDNs secreted by bacteria, or, as shown recently, through binding of a structurally distinct CDN produced by a host cell receptor in response to binding cytosolic double-stranded (ds)DNA. Although this relatively new class of adjuvants has to date only been evaluated in mice, newly available CDN-STING cocrystal structures will likely intensify efforts in this field towards further development and evaluation in human trials both in preventive vaccine and immunotherapy settings.
    11/2013; 1(4):131-143. DOI:10.1177/2051013613501988
  • [Show abstract] [Hide abstract]
    ABSTRACT: STING has emerged in recent years as an important signalling adaptor in the activation of type I interferon responses during infection with DNA viruses and bacteria. An increasing body of evidence suggests that STING also modulates responses to RNA viruses, though the mechanisms remain less clear. In this review, we give a brief overview of the ways in which STING facilitates sensing of RNA viruses. These include modulation of RIG-I-dependent responses through STING's interaction with MAVS, and more speculative mechanisms involving the DNA sensor cGAS, and sensing of membrane remodelling events. We then provide an in-depth literature review to summarise the known mechanisms by which RNA viruses of the families Flaviviridae and Coronaviridae evade sensing through STING. Our own work has shown that the NS2B/3 protease complex of the flavivirus Dengue virus binds and cleaves STING, and that an inability to degrade murine STING may contribute to host restriction in this virus. We contrast this to the mechanism employed by the distantly related hepacivirus Hepatitis C virus, in which STING is bound and inactivated by the NS4B protein. Finally, we discuss STING antagonism in the coronaviruses SARS coronavirus and Human coronavirus NL63, which disrupt K63-linked polyubiquitination and dimerisation of STING (both of which are required for STING-mediated activation of IRF-3) via their papain-like proteases. We draw parallels with less-well characterised mechanisms of STING antagonism in related viruses, and place our current knowledge in the context of species tropism restrictions that potentially affect the emergence of new human pathogens.
    Cytokine & Growth Factor Reviews 08/2014; 25(6). DOI:10.1016/j.cytogfr.2014.08.004 · 6.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cyclic dinucleotides (CDNs) play central roles in bacterial pathogenesis and innate immunity. The mammalian enzyme cGAS synthesizes a unique cyclic dinucleotide (cGAMP) containing a 2'-5' phosphodiester linkage essential for optimal immune stimulation, but the molecular basis for linkage specificity is unknown. Here, we show that the Vibrio cholerae pathogenicity factor DncV is a prokaryotic cGAS-like enzyme whose activity provides a mechanistic rationale for the unique ability of cGAS to produce 2'-5' cGAMP. Three high-resolution crystal structures show that DncV and human cGAS generate CDNs in sequential reactions that proceed in opposing directions. We explain 2' and 3' linkage specificity and test this model by reprogramming the human cGAS active site to produce 3'-5' cGAMP, leading to selective stimulation of alternative STING adaptor alleles in cells. These results demonstrate mechanistic homology between bacterial signaling and mammalian innate immunity and explain how active site configuration controls linkage chemistry for pathway-specific signaling.
    Cell 08/2014; 158(5). DOI:10.1016/j.cell.2014.07.028 · 33.12 Impact Factor

Full-text (2 Sources)

Download
7 Downloads
Available from
Dec 22, 2014