TDP-43 regulates endogenous retrovirus-K viral protein accumulation

Manghera, Mamneet; Ferguson-Parry, Jennifer; Douville, Renée N.

doi:10.1016/j.nbd.2016.06.017

Cited by 41 publications

(66 citation statements)

References 53 publications

(72 reference statements)

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“…Interestingly, protein clearance pathways, such as the proteasome system and autophagy, are dysregulated in ERVKassociated neurological diseases, including ALS (48). Recently, we demonstrated that the proteasome system and autophagy are crucial for homeostatic clearance of ERVK proteins (49). In the absence of functional protein degradation pathways, inflammationinduced ERVK aggresomes may persist and propagate chronic neuronal damage.…”

Section: Discussionmentioning

confidence: 99%

NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat

Manghera

Ferguson-Parry

Lin

et al. 2016

J Virol

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113

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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. IMPORTANCEIt 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.T housands 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 and whether their expression is relevant to cellular processes. We previously proposed that the viral promoter of endogenous retrovirus K (ERVK) is responsive to inflammatory transcription factors (1) due to the presence of two conserved interferon-stimulated response elements (ISREs). Thus, select proinflammatory transcription factors may drive ERVK expression.The transcription of integrated retroviral sequences within the human genome is regulated by viral promoters, called long terminal repeats (LTRs), flanking either side of the core viral genome. These LTRs contain transcriptional regulatory elements that are responsive to both viral and cellular transcription factors (TFs). Interferon regulatory factors (IRFs) and nu...

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Section: Discussionmentioning

confidence: 99%

NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat

Manghera

Ferguson-Parry

Lin

et al. 2016

J Virol

Self Cite

113

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“…A common event in ALS is the aberrant deposit of ubiquitinated and hyper-phosphorylated TDP-43 in the cytoplasm and nucleus of neurons ( Mackenzie et al, 2007 ; Buratti and Baralle, 2008 ). Further, formation of TDP-43 aggregates has been shown to alter HERV-K RT and polyprotein levels and cellular localization of these viral proteins ( Manghera et al, 2016a ). Measurement of TDP-43 protein expression (Protein Tech #10782-2-AP antibody) by immunohistochemistry ( Figure 1C ) or western blot analysis (data not shown) consistently show an increase in TDP-43 levels in HIV + specimens, as compared to controls.…”

Section: The Search For An Herv-k-associated Biomarkermentioning

confidence: 99%

Human Endogenous Retrovirus-K and TDP-43 Expression Bridges ALS and HIV Neuropathology

Douville

Nath

2017

Front. Microbiol.

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Despite the repetitive association of endogenous retroviruses in human disease, the mechanisms behind their pathological contributions remain to be resolved. Here we discuss how neuronal human endogenous retrovirus-K (HERV-K) expression in human immunodeficiency virus (HIV)-infected individuals is a distinct pathological aspect of HIV-associated neurological conditions, such as HIV encephalitis and HIV-associated neurocognitive disorders. Enhanced neuronal HERV-K levels were observed in the majority of HIV-infected individuals, and to a higher degree in brain tissue marked by HIV replication. Moreover, we highlight an important neuropathological overlap between amyotrophic lateral sclerosis and HIV encephalitis, that being the formation of neurotoxic TDP-43 deposits in neurons. Herein, we argue for enhanced transdisciplinary research in the field of ERV biology, using an example of how HERV-K expression has novel mechanistic and therapeutic implications for HIV neuropathology.

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“…The second possibility is that HERV protein levels are mediated by TAR DNA binding protein 43 (TDP-43), which has an important role in ALS pathophysiology (17) and has been shown to be increased in the cerebrospinal fluid (18)(19)(20)(21)(22) and blood (23) of some PALS. Based on experiments in cultured human cells, Drosophila (fruit fly) and mice TDP-43 models, it is possible that HERV RT protein levels are being increased by TDP-43 through a not yet clear mechanism (11,(24)(25)(26). Interestingly, HIV infection of the CNS also leads to neuroinflammation, increased TDP-43 expression, and increased HERV expression (27).…”

Section: Mechanismsmentioning

confidence: 99%

ALSUntangled 45: Antiretrovirals

2018

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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TDP-43 regulates endogenous retrovirus-K viral protein accumulation

Cited by 41 publications

References 53 publications

NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat

NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5′ Long Terminal Repeat

Human Endogenous Retrovirus-K and TDP-43 Expression Bridges ALS and HIV Neuropathology

ALSUntangled 45: Antiretrovirals

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