TAR DNA-Binding Protein 43 is Cleaved by the Protease 3C of Enterovirus A71

Wo, Xiaoman; Yuan, Yuan; Xu, Yong; Yang, Chen; Wang, Yao; Zhao, Shuoxuan; Lin, Lexun; Zhong, Xiaoyan; Wang, Yan; Zhong, Zhaohua; Zhao, Wenran

doi:10.1007/s12250-020-00262-x

Cited by 7 publications

(6 citation statements)

References 51 publications

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“…In addition to its role in silencing the expression of ERVs and RTEs, TDP-43 also may have a fundamental role in the cellular response to exogenous viral infection [22][23][24] . Indeed, enteroviral infection can cause pathological accumulation of TDP-43 23,24 . We therefore tested whether expression of ERVs could impact the localization and phosphorylation of TDP-43.…”

Section: Resultsmentioning

confidence: 99%

Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration

Chang

Dubnau

2023

Nat Commun

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Inter-cellular movement of “prion-like” proteins is thought to explain propagation of neurodegeneration between cells. For example, propagation of abnormally phosphorylated cytoplasmic inclusions of TAR-DNA-Binding protein (TDP-43) is proposed to underlie progression of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). But unlike transmissible prion diseases, ALS and FTD are not infectious and injection of aggregated TDP-43 is not sufficient to cause disease. This suggests a missing component of a positive feedback necessary to sustain disease progression. We demonstrate that endogenous retrovirus (ERV) expression and TDP-43 proteinopathy are mutually reinforcing. Expression of either Drosophila mdg4-ERV (gypsy) or the human ERV, HERV-K (HML-2) are each sufficient to stimulate cytoplasmic aggregation of human TDP-43. Viral ERV transmission also triggers TDP-43 pathology in recipient cells that express physiological levels of TDP-43, whether they are in contact or at a distance. This mechanism potentially underlies the TDP-43 proteinopathy-caused neurodegenerative propagation through neuronal tissue.

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Section: Resultsmentioning

confidence: 99%

Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration

Chang

Dubnau

2023

Nat Commun

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“…The molecular mechanisms underlying the embryotoxic effect of 3Cpro are currently unclear. Picornavirus 3C protease can cleave various cellular proteins including regulatory factors, which can affect a wide range of biochemical processes [1][2][3][4][5][6][7][8] . It is worth mentioning that 3C protease activity induces cell death [9][10][11][12][13][14][15][16][17][18] , and thus can be considered as the key factor of viral cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Embryotoxic activity of 3C protease of human hepatitis A virus in developing Danio rerio embryos

Selina

Karaseva

Komissarov

et al. 2021

Sci Rep

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The 3C protease is a key factor in picornavirus-induced pathologies with a comprehensive action on cell targets. However, the effects induced by the enzyme have not been described at the organismic level. Here, the model of developing Danio rerio embryos was used to analyze possible toxic effects of the 3C protease of human hepatitis A virus (3Cpro) at the whole-body level. The transient 3Cpro expression had a notable lethal effect and induced a number of specific abnormalities in Danio rerio embryos within 24 h. These effects are due to the proteolytic activity of the enzyme. At the same time, the 3Cpro variant with reduced catalytic activity (3Cmut) increased the incidence of embryonic abnormalities; however, this effect was smaller compared to the native enzyme form. While the expression of 3Cmut increased the overall rate of abnormalities, no predominance of specific ones was observed. The data obtained point to a presence significant impact of picornavirus 3Cprotease at the whole-organism level and make contribution to the study of the infectious process caused by human hepatitis A virus.

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“…This has been shown in Drosophila, human neuroblastoma cells, and cortical tissue from human subjects [12][13][14][15][16][17][18][19][20][21] . In addition to its role in silencing the expression of ERVs and RTEs, TDP-43 also may have a fundamental role in the cellular response to exogenous viral infection [22][23][24] . Indeed, enteroviral infection can cause pathological accumulation of TDP-43 23,24 .…”

Section: Human Herv-k and Drosophila Gypsy-erv (Mdg4-erv) Can Trigger...mentioning

confidence: 99%

Endogenous Retroviruses and TDP-43 Proteinopathy Form a Sustaining Feedback to Drive the Intercellular Spread of Neurodegeneration

Chang

Dubnau

2022

Preprint

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Neurodegenerative disorders are thought to initiate focally and then spread over time through neural circuits. A mechanism that has been proposed to explain this is the inter-cellular movement of misfolded “prion-like” proteins that then recruit normally folded proteins in recipient cells to also adopt pathological conformations. Such a mechanism has been proposed, for example, to explain the propagation of abnormally phosphorylated cytoplasmic inclusions of TAR-DNA-Binding protein (TDP-43) during the progression of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). But unlike transmissible prion diseases such as mad cow disease, which can be caused by ingestion or by injection into animal brains of misfolded PrP, ALS and FTD are not infectious and the injection of phosphorylated and aggregated TDP-43 protein into rodent brains is not sufficient to cause disease phenotypes unless those animals also express high levels of transgenic TDP-43 protein. This suggests a missing component of a positive feedback that is necessary to sustain disease progression. We provide evidence that endogenous retroviruses (ERVs) are that missing component. We demonstrate that ERV expression and TDP-43 proteinopathy are mutually reinforcing. Expression of either the Drosophila ERV, gypsy (mdg4) or the human ERV, HERV-K (HML-2) are each sufficient to stimulate cytoplasmic aggregation of human TDP-43. Importantly. We also demonstrate that viral ERV transmission causes propagation of such TDP-43 pathology to cells that express physiological levels of TDP-43, whether they are in contact or at a distance. This mechanism underlies the toxicity of glial cells to neurons and other glia in a Drosophila in vivo model.

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TAR DNA-Binding Protein 43 is Cleaved by the Protease 3C of Enterovirus A71

Cited by 7 publications

References 51 publications

Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration

Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration

Embryotoxic activity of 3C protease of human hepatitis A virus in developing Danio rerio embryos

Endogenous Retroviruses and TDP-43 Proteinopathy Form a Sustaining Feedback to Drive the Intercellular Spread of Neurodegeneration

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