Nuclear trafficking of Anelloviridae capsid protein ORF1 reflects modular evolution of subcellular targeting signals
Petersen, Gayle F., Pavan, Silvia, Ariawan, Daryl, Tietz, Ole, Nematollahzadeh, Sepehr, Sarker, Subir, Forwood, Jade, and Alvisi, Gualtiero (2025) Nuclear trafficking of Anelloviridae capsid protein ORF1 reflects modular evolution of subcellular targeting signals. Virus Evolution, 11 (1). veaf069.
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Abstract
Anelloviridae members are ubiquitous viruses with a small, negative sense, single-stranded DNA genome which is replicated by host cell DNA polymerases. Anelloviruses are postulated to interact with the host cell nuclear transport machinery, however, the lack of reliable cell culture models strongly limits our knowledge regarding Anelloviridae-host interactions. In particular, capsid nuclear import is a largely uncharacterized process. We addressed this by investigating the relationship between host cell nuclear transport receptors (NTRs) and ORF1, the putative capsid protein from torque teno douroucouli virus (TTDoV). We identified the subcellular targeting signals and NTRs responsible for its nucleolar and nuclear localization, and characterized their relative contribution to ORF1 subcellular localization. In the absence of other viral proteins, ORF1 accumulated in the nucleoli. Bioinformatics analysis revealed a putative classical nuclear localization signal (cNLS) within the highly conserved N-terminal arginine rich motif (ARM) ('NLSn', 27-RRWRRRPRRRRRPYRRRPYRRYGRRRKVRRR-57), and an additional C-terminal cNLS ('NLSc', 632-LPPPEKRARWGF-643), which has been specifically acquired by Anelloviridae capsids with larger projection domains. Such NLSs play distinct roles in ORF1 subcellular localization by interacting with specific NTRs. NLSn, a non-classical NLS, features broad importin (IMP) binding affinity yet plays a minor role in nuclear import, being responsible for nucleolar targeting likely through interaction with nucleolar components. NLSc, a bona fide cNLS, specifically interacts with IMPα and is the main driver of active nuclear transport in an IMPα/β1-dependent fashion. These findings suggest an evolutionary correlation between the acquisition of progressively larger projection domains and the presence of additional cNLSs in Anelloviridae capsids, aimed at maximizing IMPα/β1-mediated nuclear import.
| Item ID: | 89160 |
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| Item Type: | Article (Research - C1) |
| ISSN: | 2057-1577 |
| Keywords: | Anelloviridae, capsid, karyopherins, NLS, NoLS, nucleolus, projection domain, shuttling |
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| Copyright Information: | © The Author(s) 2025. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. |
| Funders: | Australian Research Council (ARC) |
| Projects and Grants: | ARC DE200100367 |
| Date Deposited: | 22 Oct 2025 02:30 |
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