Trichodysplasia spinulosa polyomavirus small T antigen synergistically modulates S6 protein translation and DNA damage response pathways to shape host cell environment
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature..
TSPyV is a viral agent linked to Trichodysplasia spinulosa, a disfiguring human skin disease which presents with hyperkeratotic spicule eruption in immunocompromised hosts. This proliferative disease state requires extensive modulation of the host cell environment. While the small T (sT) antigen of TSPyV has been postulated to cause widespread cellular perturbation, its specific substrates and their mechanistic connection are unclear. To identify the cellular substrates and pathways perturbed by TSPyV sT and propose a nuanced model that reconciles the multiple arms of TSPyV pathogenesis, changes in expression of several proteins and phospho-proteins in TSPyV sT expressing and TSPyV sT deletion mutant-expressing cell lysates were interrogated using Western blot assays. TSPyV sT expression exploits the DNA damage response pathway, by inducing hyperphosphorylation of ATM and 53BP1 and upregulation of BMI-1. Concurrently, sT dysregulates the S6 protein translation pathway via hyperphosphorylation of CDC2, p70 S6 kinase, S6, and PP1α. The S6S244/247 and p-PP1αT320 phospho-forms are points of overlap between the DDR and S6 networks. We propose a mechanistic rationale for previous reports positioning sT antigen as the key driver of TSPyV pathogenesis. We illuminate novel targets in the S6 and DDR pathways and recognize a potential synergy between these pathways. TSPyV may sensitize the cell to both unrestricted translation and genomic instability. This multi-pronged infection model may inform future therapeutic modalities against TSPyV and possibly other viruses with overlapping host substrates.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:58 |
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| Enthalten in: |
Virus genes - 58(2022), 1 vom: 08. Feb., Seite 35-41 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Narayanan, Deepika [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.03.2022 Date Revised 16.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s11262-021-01880-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. | ||
| 520 | |a TSPyV is a viral agent linked to Trichodysplasia spinulosa, a disfiguring human skin disease which presents with hyperkeratotic spicule eruption in immunocompromised hosts. This proliferative disease state requires extensive modulation of the host cell environment. While the small T (sT) antigen of TSPyV has been postulated to cause widespread cellular perturbation, its specific substrates and their mechanistic connection are unclear. To identify the cellular substrates and pathways perturbed by TSPyV sT and propose a nuanced model that reconciles the multiple arms of TSPyV pathogenesis, changes in expression of several proteins and phospho-proteins in TSPyV sT expressing and TSPyV sT deletion mutant-expressing cell lysates were interrogated using Western blot assays. TSPyV sT expression exploits the DNA damage response pathway, by inducing hyperphosphorylation of ATM and 53BP1 and upregulation of BMI-1. Concurrently, sT dysregulates the S6 protein translation pathway via hyperphosphorylation of CDC2, p70 S6 kinase, S6, and PP1α. The S6S244/247 and p-PP1αT320 phospho-forms are points of overlap between the DDR and S6 networks. We propose a mechanistic rationale for previous reports positioning sT antigen as the key driver of TSPyV pathogenesis. We illuminate novel targets in the S6 and DDR pathways and recognize a potential synergy between these pathways. TSPyV may sensitize the cell to both unrestricted translation and genomic instability. This multi-pronged infection model may inform future therapeutic modalities against TSPyV and possibly other viruses with overlapping host substrates | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a DNA damage response | |
| 650 | 4 | |a Molecular virology | |
| 650 | 4 | |a Pathogenesis | |
| 650 | 4 | |a Translational regulation | |
| 650 | 4 | |a Trichodysplasia spinulosa (TS) | |
| 650 | 4 | |a Trichodysplasia spinulosa-associated polyomavirus (TSPyV) | |
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| 700 | 1 | |a Simonette, Rebecca |e verfasserin |4 aut | |
| 700 | 1 | |a Rady, Peter L |e verfasserin |4 aut | |
| 700 | 1 | |a Tyring, Stephen K |e verfasserin |4 aut | |
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