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Trichodysplasia spinulosa polyomavirus small T antigen synergistically modulates S6 protein translation and DNA damage response pathways to shape host cell environment

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Abstract

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.

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Abbreviations

TSPyV:

Trichodysplasia spinulosa polyomavirus

TS:

Trichodysplasia spinulosa

sT:

Small tumor

MCPyV:

Merkel cell polyomavirus

DDR:

DNA damage response

ATM:

Ataxia-telangiectasia mutated

ATR:

ATM and Rad3-related

PVDF:

Polyvinylidene difluoride

PP1α:

Protein phosphatase 1 α

p-53BP1:

P53-binding protein 1

NHEJ:

Non-homologous end-joining

BMI-1:

B-cell specific moloney murine virus integration site 1

DSB:

Double-stranded breaks

HR:

Homologous recombination

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Author notes

  1. Deepika Narayanan and Danyal Tahseen: Co-First Author

Authors and Affiliations

  1. Department of Dermatology, McGovern Medical School at UT Health Science Center, 6431 Fannin Street, Houston, TX, 77030, USA

    Deepika Narayanan, Danyal Tahseen, Brooke R. Bartley, Stephen A. Moore, Rebecca Simonette, Peter L. Rady & Stephen K. Tyring

  2. Rice University, Houston, TX, USA

    Stephen A. Moore

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Contributions

DN: design of the project, analysis and interpretation of data, drafting and revising the manuscript, final approval of the manuscript to be published, and agreement to be accountable for all aspects of the work. DT: acquisition of data, drafting and revising the manuscript, final approval of the manuscript to be published, and agreement to be accountable for all aspects of the work. BRB: acquisition of data, revising the manuscript, final approval of the manuscript to be published, and agreement to be accountable for all aspects of the work. SAM: acquisition of data, revising the manuscript, final approval of the manuscript to be published, and agreement to be accountable for all aspects of the work. RAS: acquisition and analysis of data, revising the manuscript, final approval of the manuscript to be published, and agreement to be accountable for all aspects of the work. PLR: design of the project, analysis and interpretation of data, revising the manuscript, final approval of the manuscript to be published, and agreement to be accountable for all aspects of the work. SKT: design of the project, analysis and interpretation of data, revising the manuscript, final approval of the manuscript to be published, and agreement to be accountable for all aspects of the work.

Corresponding author

Correspondence to Stephen K. Tyring.

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Ethical approval was not required because no identifiable human or animal material was used in this study.

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Edited by Wolfram H. Gerlich.

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Narayanan, D., Tahseen, D., Bartley, B.R. et al. Trichodysplasia spinulosa polyomavirus small T antigen synergistically modulates S6 protein translation and DNA damage response pathways to shape host cell environment. Virus Genes 58, 35–41 (2022). https://doi.org/10.1007/s11262-021-01880-7

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