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Mechanistic insights into an ancient adenovirus precursor protein VII shows multiple nuclear import receptor pathways
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  • Gualtiero Alvisi,
  • Sepehr Nematollahzadeh,
  • Ajani Athukorala,
  • Camilla M. Donnelly,
  • Silvia Pavan,
  • Victoria Atelie-Djossou,
  • Enzo Di Iorio,
  • Babu Nath,
  • Karla J. Helbig,
  • Brian McSharry,
  • Jade K. Forwood,
  • Subir Sarker
Gualtiero Alvisi
Universita degli Studi di Padova Dipartimento di Medicina Molecolare

Corresponding Author:[email protected]

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Sepehr Nematollahzadeh
Universita degli Studi di Padova Dipartimento di Medicina Molecolare
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Ajani Athukorala
La Trobe University Department of Microbiology Anatomy Physiology and Pharmacology
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Camilla M. Donnelly
Charles Sturt University School of Dentistry and Health Sciences Wagga Wagga Campus
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Silvia Pavan
Universita degli Studi di Padova Dipartimento di Medicina Molecolare
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Victoria Atelie-Djossou
Universita degli Studi di Padova Dipartimento di Medicina Molecolare
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Enzo Di Iorio
Universita degli Studi di Padova Dipartimento di Medicina Molecolare
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Babu Nath
Charles Sturt University School of Dentistry and Health Sciences Wagga Wagga Campus
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Karla J. Helbig
La Trobe University Department of Microbiology Anatomy Physiology and Pharmacology
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Brian McSharry
Charles Sturt University School of Dentistry and Health Sciences Wagga Wagga Campus
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Jade K. Forwood
Charles Sturt University School of Dentistry and Health Sciences Wagga Wagga Campus
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Subir Sarker
La Trobe University Department of Microbiology Anatomy Physiology and Pharmacology
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Abstract

Adenoviral pVII proteins are multifunctional, highly basic, histone-like proteins that can bind to and transport the viral genome into the host cell nucleus. Despite the identification of several nuclear localization signals (NLSs) in the pVII protein of human adenovirus 5 (HAdV5), the mechanistic details of nuclear transport are largely unknown. Here we provide a full characterization of the nuclear import of precursor (Pre-) pVII protein from an ancient siadenovirus, frog siadenovirus 1 (FrAdV1) using a combination of structural, functional and biochemical approaches. Two strong NLSs (termed NLSa and NLSd) interact with importin (IMP)b and IMPa respectively, and are the main drivers of nuclear import. A weaker NLS (termed NLSb) also contributes, together with an additional signal (NLSc) which we found to be important for nucleolar targeting. Expression of Pre-pVII wild-type and NLS defective derivatives in the presence of selective inhibitors of different nuclear import pathways revealed that, unlike its human counterpart, FrAdV1 Pre-pVII nuclear import is dependent on IMPa/b and IMPb1. Clearly, AdVs evolved to maximise the nuclear import pathways for the pVII proteins, whose subcellular localization is the result of a complex process. Therefore, our results pave the way for an evolutionary comparison of the interaction of different AdVs with the host cell nuclear transport machinery.
05 Feb 2024Submitted to Traffic
05 Feb 2024Submission Checks Completed
05 Feb 2024Assigned to Editor
15 Mar 2024Review(s) Completed, Editorial Evaluation Pending
18 Mar 2024Reviewer(s) Assigned
09 Jul 20241st Revision Received
11 Jul 2024Submission Checks Completed
11 Jul 2024Assigned to Editor
11 Jul 2024Review(s) Completed, Editorial Evaluation Pending
11 Jul 2024Reviewer(s) Assigned
30 Jul 2024Editorial Decision: Accept