TDP-43 regulates endogenous retrovirus-K viral protein accumulation
- PMID: 27370226
- DOI: 10.1016/j.nbd.2016.06.017
TDP-43 regulates endogenous retrovirus-K viral protein accumulation
Abstract
The concomitant expression of neuronal TAR DNA binding protein 43 (TDP-43) and human endogenous retrovirus-K (ERVK) is a hallmark of ALS. Since the involvement of TDP-43 in retrovirus replication remains controversial, we sought to evaluate whether TDP-43 exerts an effect on ERVK expression. In this study, TDP-43 bound the ERVK promoter in the context of inflammation or proteasome inhibition, with no effect on ERVK transcription. However, over-expression of ALS-associated aggregating forms of TDP-43, but not wild-type TDP-43, significantly enhanced ERVK viral protein accumulation. Human astrocytes and neurons further demonstrated cell-type specific differences in their ability to express and clear ERVK proteins during inflammation and proteasome inhibition. Astrocytes, but not neurons, were able to clear excess ERVK proteins through stress granule formation and autophagy. In vitro findings were validated in autopsy motor cortex tissue from patients with ALS and neuro-normal controls. We further confirmed marked enhancement of ERVK in cortical neurons of patients with ALS. Despite evidence of enhanced stress granule and autophagic response in ALS cortical neurons, these cells failed to clear excess ERVK protein accumulation. This highlights how multiple cellular pathways, in conjunction with disease-associated mutations, can converge to modulate the expression and clearance of viral gene products from genomic elements such as ERVK. In ALS, ERVK protein aggregation is a novel aspect of TDP-43 misregulation contributing towards the pathology of this neurodegenerative disease.
Keywords: Amyotrophic lateral sclerosis (ALS); Autophagy; Endogenous retrovirus (ERVK); Stress granule; TAR DNA-binding protein 43 (TDP-43).
Copyright © 2016 Elsevier Inc. All rights reserved.
Similar articles
-
The Molecular Link Between TDP-43, Endogenous Retroviruses and Inflammatory Neurodegeneration in Amyotrophic Lateral Sclerosis: a Potential Target for Triumeq, an Antiretroviral Therapy.Mol Neurobiol. 2023 Nov;60(11):6330-6345. doi: 10.1007/s12035-023-03472-y. Epub 2023 Jul 14. Mol Neurobiol. 2023. PMID: 37450244 Free PMC article. Review.
-
NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5' Long Terminal Repeat.J Virol. 2016 Sep 29;90(20):9338-49. doi: 10.1128/JVI.01503-16. Print 2016 Oct 15. J Virol. 2016. PMID: 27512062 Free PMC article.
-
Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis.Ann Neurol. 2011 Jan;69(1):141-51. doi: 10.1002/ana.22149. Ann Neurol. 2011. PMID: 21280084 Free PMC article.
-
Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K.Cells. 2020 Jun 30;9(7):1584. doi: 10.3390/cells9071584. Cells. 2020. PMID: 32629888 Free PMC article.
-
The debated toxic role of aggregated TDP-43 in amyotrophic lateral sclerosis: a resolution in sight?Brain. 2019 May 1;142(5):1176-1194. doi: 10.1093/brain/awz078. Brain. 2019. PMID: 30938443 Free PMC article. Review.
Cited by
-
Species-Specific Transcription Factors Associated with Long Terminal Repeat Promoters of Endogenous Retroviruses: A Comprehensive Review.Biomolecules. 2024 Feb 26;14(3):280. doi: 10.3390/biom14030280. Biomolecules. 2024. PMID: 38540701 Free PMC article. Review.
-
Transposable Elements: Emerging Therapeutic Targets in Neurodegenerative Diseases.Neurotox Res. 2024 Jan 25;42(1):9. doi: 10.1007/s12640-024-00688-1. Neurotox Res. 2024. PMID: 38270797 Review.
-
Implications of TDP-43 in non-neuronal systems.Cell Commun Signal. 2023 Nov 23;21(1):338. doi: 10.1186/s12964-023-01336-5. Cell Commun Signal. 2023. PMID: 37996849 Free PMC article. Review.
-
Ribonucleoprotein Granules: Between Stress and Transposable Elements.Biomolecules. 2023 Jun 23;13(7):1027. doi: 10.3390/biom13071027. Biomolecules. 2023. PMID: 37509063 Free PMC article. Review.
-
The Molecular Link Between TDP-43, Endogenous Retroviruses and Inflammatory Neurodegeneration in Amyotrophic Lateral Sclerosis: a Potential Target for Triumeq, an Antiretroviral Therapy.Mol Neurobiol. 2023 Nov;60(11):6330-6345. doi: 10.1007/s12035-023-03472-y. Epub 2023 Jul 14. Mol Neurobiol. 2023. PMID: 37450244 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous