Structure and function of the RNA polymerase complex of Borna disease virus, a nuclear-replicating non-segmented negative-strand RNA virus - Abstract

Sep 29, 2026

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Borna disease virus 1 (BoDV-1) is a non-segmented negative-strand RNA virus that uniquely replicates in the nucleus of mammalian host cells, unlike most related viruses that replicate in the cytoplasm. The molecular basis for this nuclear replication by the RNA-dependent RNA polymerase (RdRp) complex is not well understood. The work reports a 2.8 Å cryo-EM structure of the BoDV-1 RdRp complex and defines how L and tetrameric P coordinate initiation of internal de novo RNA synthesis and transcription initiation efficiency.

LanguageEnglish

CategoryResearch & Report

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Reading Time43 min

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Abstract

Introduction

Background on non-segmented negative-strand RNA viruses

Nuclear replication of bornaviruses

Importance of understanding bornavirus strategies

RdRp organization in NNS RNA viruses

Nucleic Acids Research, 2026, 54, gkaf1413 [https://doi.org/10.1093/nar/gkaf1413](https://doi.org/10.1093/nar/gkaf1413) Nucleic Acid Enzymes Structure and function of the RNA polymerase complex of Borna disease virus, a nuclear-replicating non-segmented negative-strand RNA virus Eric Gibbs1 ,†, Minako Ogino2 ,†, Takehiro Kanda3,4 ,†, Dean Watkins2,5 , Kyle Whiddon6 , Keizo Tomonaga3,4,7 ,* , Sudha Chakrapani1,6 ,* , Tomoaki Ogino 2 ,* 1 Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States 2 Department of Medical Microbiology and Immunology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, United States 3 Laboratory of RNA viruses, Department of Virus Research, Institution for Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan 4 Department of Molecular Virology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan 5 Present address: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States 6 Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, OH 44106, United States 7 Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan ∗ To whom correspondence should be [addressed. Email:](addressed. Email:tomonaga.keizo.5r@kyoto-u.ac.jp)[tomonaga.keizo.5r@kyoto-u.ac.jp](addressed. Email:tomonaga.keizo.5r@kyoto-u.ac.jp) Correspondence may also be addressed to Sudha [Chakrapani. Email:](Chakrapani. Email:sudha.chakrapani@case.edu)[sudha.chakrapani@case.edu](Chakrapani. Email:sudha.chakrapani@case.edu) Correspondence may also be addressed to Tomoaki [Ogino. Email:](Ogino. Email:tomoaki.ogino@utoledo.edu)[tomoaki.ogino@utoledo.edu](Ogino. Email:tomoaki.ogino@utoledo.edu)[ ](Ogino. Email:tomoaki.ogino@utoledo.edu)†These authors contributed equally to this work. Abstract Borna disease virus 1 (BoDV-1) is a non-segmented negative-strand (NNS) RNA virus that uniquely replicates in the nucleus of mammalian host cells, in contrast to most NNS RNA viruses that replicate in the cytoplasm. The mechanisms underlying nuclear replication of BoDV-1 and related bornaviruses with their RNA-dependent RNA polymerase (RdRp) complexes remain poorly understood. Here, we report the 2.8 ˚A cryo-EM structure of the BoDV-1 RdRp complex, comprising the large (L) protein and tetrameric phosphoprotein (P) . The L protein features an N-terminal superdomain containing the RdRp and GDP polyribonucleotidyltransferase (PRNTase, mRNA-capping enzyme) domains, along with three Cterminal appendages, including a methyltransferase-like domain. The RdRp initiates de novo RNA synthesis internally at the genomic promoter, producing 5􀀃-triphosphorylated transcripts corresponding to the 5􀀃 end of the anti-genome. P interacts with the fingers RdRp subdomain of L. Structure-guided mutagenesis shows that the residues involved in the L–P interaction are essential for efficient transcription initiation and, consequently, for viral gene expression. A flexible loop within the PRNTase domain, analogous to the rhabdovirus priming-capping loop, appears critical for transcription initiation. These findings provide the structural and functional insights into the BoDV-1 RdRp and support a shared evolutionary origin between nuclear and cytoplasmic NNS RNA viruses. Graphical abstract Introduction Non-segmented negative-strand (NNS) RNA viruses belonging to the order Mononegavirales are highly diversified eukaryotic viruses, including significant human pathogens, such as rabies (rhabdovirus), Nipah (paramyxovirus), respiratory syncytial (pneumovirus), and Ebola (filovirus) [1] . Most NNS RNA viruses replicate in the cytoplasm of host cells, whereas bornaviruses, such as Borna disease virus 1 (BoDV-1), replicate in the nucleus [2] . BoDV-1 is a causative agent of Born

FAQs

What makes BoDV-1 distinct from most non-segmented negative-strand RNA viruses?

BoDV-1 uniquely replicates in the nucleus of mammalian host cells, whereas most non-segmented negative-strand RNA viruses replicate in the cytoplasm.

What structural method and resolution were used to study the BoDV-1 RdRp complex?

A cryo-EM structure of the BoDV-1 RdRp complex was determined at 2.8 Å resolution.

How does the RdRp complex initiate RNA synthesis during transcription?

The RdRp initiates de novo RNA synthesis internally at the genomic promoter, producing 5'-triphosphorylated transcripts corresponding to the 5' end of the anti-genome.

Sep 29, 2026

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