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NF-?B and IRF1 Induce Endogenous Retrovirus K Expression via
Interferon-Stimulated Response Elements in Its 5 Long Terminal Repeat
#MMPMID27512062
Manghera M
; Ferguson-Parry J
; Lin R
; Douville RN
J Virol
2016[Oct]; 90
(20
): 9338-49
PMID27512062
show ga
Thousands of endogenous retroviruses (ERV), viral fossils of ancient germ line
infections, reside within the human genome. Evidence of ERV activity has been
observed widely in both health and disease. While this is most often cited as a
bystander effect of cell culture or disease states, it is unclear which signals
control ERV transcription. Bioinformatic analysis suggests that the viral
promoter of endogenous retrovirus K (ERVK) is responsive to inflammatory
transcription factors. Here we show that one reason for ERVK upregulation in
amyotrophic lateral sclerosis (ALS) is the presence of functional
interferon-stimulated response elements (ISREs) in the viral promoter.
Transcription factor overexpression assays revealed independent and synergistic
upregulation of ERVK by interferon regulatory factor 1 (IRF1) and NF-?B isoforms.
Tumor necrosis factor alpha (TNF-?) and LIGHT cytokine treatments of human
astrocytes and neurons enhanced ERVK transcription and protein levels through
IRF1 and NF-?B binding to the ISREs. We further show that in ALS brain tissue,
neuronal ERVK reactivation is associated with the nuclear translocation of IRF1
and NF-?B isoforms p50 and p65. ERVK overexpression can cause motor neuron
pathology in murine models. Our results implicate neuroinflammation as a key
trigger of ERVK provirus reactivation in ALS. These molecular mechanisms may also
extend to the pathobiology of other ERVK-associated inflammatory diseases, such
as cancers, HIV infection, rheumatoid arthritis, and schizophrenia. IMPORTANCE:
It has been well established that inflammatory signaling pathways in ALS converge
at NF-?B to promote neuronal damage. Our findings suggest that
inflammation-driven IRF1 and NF-?B activity promotes ERVK reactivation in neurons
of the motor cortex in ALS. Thus, quenching ERVK activity through antiretroviral
or immunomodulatory regimens may hinder virus-mediated neuropathology and improve
the symptoms of ALS or other ERVK-associated diseases.
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