Laboratory of Persistent Viral Diseases, Rocky Mountain
Laboratories, NIAID, NIH, 903 S. Fourth St., Hamilton, MT59840.
sbest@niaid.nih.gov.
The tick-borne encephalitis (TBE) complex of viruses, genus Flavivirus, can cause severe encephalitis, meningitis,
and/or hemorrhagic fevers. Effective interferon (IFN) responses are
critical to recovery from infection with flaviviruses,
and the mosquito-borne flaviviruses can inhibit
this response. However, little is known about interactions between IFN
signaling and TBE viruses. Langat virus (LGTV), a
member of the TBE complex of viruses, was found to be highly sensitive to
the antiviral effects of IFN. However, LGTV infection inhibited IFN-induced
expression of a reporter gene driven by either IFN-alpha/beta- or
IFN-gamma-responsive promoters. This indicated that LGTV can inhibit the
IFN-mediated JAK-STAT (Januskinase-signal
transducer and activator of transcription) pathway of signal transduction.
The mechanism of inhibition was due to blocks in the phosphorylation
of both Januskinases,
Jak1 and Tyk2, during IFN-alpha signaling and at least a failure of Jak1 phosphorylation following IFN-gamma stimulation. To
determine the viral protein(s) responsible, we individually expressed all
nonstructural (NS) proteins and examined their ability to inhibit signal
transduction. Expression of NS5 alone inhibited STAT1 phosphorylation
in response to IFN, thus identifying NS5 as a potential IFN antagonist. Examination
of interactions between NS5 and cellular proteins revealed that NS5
associated with IFN-alpha/beta and -gamma receptor complexes. Importantly,
inhibition of JAK-STAT signaling and NS5-IFN receptor interactions were
demonstrated in LGTV-infected human monocyte-derived
dendritic cells, important target cells for early
virus replication. Because NS5 may interfere with both innate and acquired
immune responses to virus infection, this protein may have a significant
role in viral pathogenesis.
PMID: 16188985 [PubMed - in process]
The FMR2 gene is dysregulated
by the fragile X E triplet repeat expansion in patients with FRAXE mental retardation
syndrome. A CCG triplet, located in the 5' untranslated
region of the FRAXE gene undergoes expansion and methylation
in these patients, eliminating detectable gene transcription. FRAXE
syndrome is distinct from fragile X syndrome, a more common genetic form of
mental retardation caused by expansion and methylation
of a similar repeat in the FMR1 gene located 600 kb proximal to FRAXE.
FRAXE syndrome is rare, and patients' phenotypes are highly variable,
leading to difficulties with predicting specific FMR2 functions based on
the human disease. Recently, Lilliputian(Lilli), a Drosophila FMR2 orthologue,
was identified; this gene has been linked with several signal transduction
pathways, including the transforming growth factor-beta (TGF-beta) pathway,
the Raf/MEK/MAP kinase
(MAPK) pathway, and the P13K/PKB pathway. Mutation of Lilli
shows defects in germinal band extension, cytoskeletal
structure, cell growth, and organ development. The Lilli
gene suggests possible functions for FMR2 (and related genes) in humans and
mice, but cannot predict specific functions. Modeling FMR2 mutation in the
mouse will be useful to understand specific functions of this gene in
vertebrates. This review presents what has been learned thus far from the
FMR2 knockout mouse model and suggests future studies on this model in
order to compare it with the human FRAXE mental retardation disorder, Lilli mutants in Drosophila and other mouse models of
genes in this family. Copyright 2003 S. Karger
AG, Basel
The gene for the alpha isoform
of the catalytic subunit of human protein phosphatase
2A (PPP2CA) was localized to chromosome 5 using somatic cell hybrids, and
then more finely mapped to chromosome region 5q23-->q31 by in situ
hybridization using a tritiatedcDNA probe. The gene for the beta isoform
of the catalytic subunit of this enzyme (PPP2CB) was mapped by the
polymerase chain reaction to human chromosome 8 using somatic cell hybrids.
Fluorescence in situ hybridization was then used to localize the PPP2CB
gene to 8p12-->p11.2, using a mixture of three genomic probes that
ranged from 3.5 to 8 kb in size. Finally, Southern blot analysis of somatic
cell hybrid DNA suggested that a PPP2CB catalytic subunit pseudogene (PPP2CBP) is on chromosome 16.
