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The Mechanism Underlying the Organization of Borna Disease Virus Inclusion

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The Mechanism Underlying the Organization of Borna Disease Virus Inclusion bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445377; this version posted May 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 The mechanism underlying the organization of Borna disease virus inclusion 2 bodies is unique among mononegaviruses 3 4 Yuya Hiraia*, Keizo Tomonagab,c,d*, Masayuki Horieb,e,f* 5 6 aDepartment of Biology, Osaka Dental University, 8-1, Kuzuha Hanazono-cho, Hirakata, Osaka 573- 7 1121, Japan. 8 bLaboratory of RNA viruses, Department of Virus Research, Institute for Frontier Life and Medical 9 Sciences (InFRONT), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, 10 Japan 11 cLaboratory of RNA Viruses, Department of Mammalian Regulatory Network, Graduate School of 12 Biostudies, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, 606-8507 Kyoto, Japan. 13 dDepartment of Molecular Virology, Graduate School of Medicine, Kyoto University, 53 Kawahara- 14 cho, Shogoin, Sakyo-ku, 606-8507 Kyoto, Japan. 15 eHakubi Center for Advanced Research, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, 16 Kyoto 606-8507, Japan 17 fLaboratory of Veterinary Microbiology, Division of Veterinary Sciences, Graduate School of Life and 18 Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-oraikita, Izumisano, Osaka 598- 19 8531, JAPAN 20 21 *Corresponding authors: 22 Yuya Hirai, PhD 23 E-mail: [email protected] 24 25 Keizo Tomonaga, DVM, PhD 26 E-mail: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445377; this version posted May 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 27 Masayuki Horie, DVM, PhD 28 Email: [email protected] 29 30 Keywords 31 Borna disease virus; non-segmented negative-strand RNA viruses; mononegavirus, 32 nucleoprotein; phosphoprotein; liquid-liquid phase separation; intrinsically disordered 33 regions; biomolecular condensates; membraneless organelles; nucleus; liquid droplets 34 35 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445377; this version posted May 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 36 Abstract 37 Inclusion bodies (IBs) are characteristic biomolecular condensates organized by 38 mononegaviruses. Here, we characterize the IBs of Borna disease virus 1 (BoDV-1), a 39 unique mononegavirus that forms IBs in the nucleus, in terms of liquid-liquid phase 40 separation (LLPS). The BoDV-1 phosphoprotein (P) alone induces LLPS and the 41 nucleoprotein (N) is incorporated into the P droplet in vitro. In contrast, co-expression of 42 N and P is required for the formation of IB-like structure in cells. Furthermore, while 43 BoDV-1 P binds to RNA, an excess amount of RNA dissolves the liquid droplets formed 44 by N and P. Notably, the N-terminal intrinsically disordered region of BoDV-1 P is 45 essential to drive LLPS and bind to RNA, suggesting that both abilities could compete 46 with one another. These features are unique among mononegaviruses, and thus this study 47 will contribute to a deeper understanding of LLPS-driven organization and RNA- 48 mediated regulation of biomolecular condensates. 49 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445377; this version posted May 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 50 Introduction 51 The order Mononegavirales contains many pathogens of great importance to public health, 52 such as measles virus, Ebola virus, rabies virus, and human respiratory syncytial virus 53 (RSV) 1. These mononegaviruses form various types of inclusion bodies (IBs) in infected 54 cells, which are thought to be the sites of viral replication 2. The IBs of mononegaviruses 55 are membraneless organelles, also called biomolecular condensates 3–6. Growing 56 evidence has shown that the IBs of several mononegaviruses, such as rabies virus 7, 57 vesicular stomatitis virus (VSV) 8, measles virus 9,10, and RSV 11, are organized by liquid- 58 liquid phase separation (LLPS). 59 The viral ribonucleoprotein (vRNP) complexes of mononegaviruses, which function 60 as the fundamental units of transcription and replication, consist of viral genomic RNA, 61 nucleoprotein (N), phosphoprotein (P), and large RNA-dependent RNA polymerase (L). 62 Among the components of vRNP complexes, the expression of N and P is sufficient for 63 the formation of IBs of rabies virus 7, measles virus 9, RSV 11, human metapneumovirus 64 12, and human parainfluenza virus 3 13. Previous studies of these IBs have provided 65 insights into the viral replication strategies, thereby contributing to the control of viral 66 infectious diseases. Additionally, since viruses exploit the host machinery for replication, 67 further studies would be helpful to gain a deeper understanding of the molecular 68 condensates in cells. 69 Borna disease virus 1 (BoDV-1) is a prototype virus of the family Bornaviridae of 70 the order Mononegavirales, which causes fatal encephalitis in mammals, including 71 humans 14. BoDV-1 is a unique mononegavirus as replication occurs in the nucleus of the 72 infected cell, whereas that of most mononegaviruses occurs in the cytoplasm 15. 73 Consequently, the IBs of cytoplasmic mononegaviruses are formed in the cytoplasm, 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445377; this version posted May 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 74 while those of BoDV-1, termed as viral speckle of transcripts (vSPOTs), are organized in 75 the nucleus 16. The vSPOTs are membraneless spherical structures containing the viral 76 genome, antigenome, and several viral proteins. The BoDV-1 genome encodes six genes, 77 N, P, matrix protein (M), envelope glycoprotein (G), L, and accessory protein (X), among 78 which N, P, M, L, and X are localized in the vSPOTs 17,18. 79 Although present in the nucleus, the vSPOTs share common properties with those of 80 the other mononegaviruses, such as membraneless structures, and their components. 81 However, the surrounding environment is important for the formation of biomolecular 82 condensates. As described above, BoDV-1 forms IBs in the cell nucleus, where the 83 surrounding environment differs from that of the cytoplasm. Thus, the IBs of BoDV-1 84 may be formed by a different mechanism from those of other cytoplasmic 85 mononegaviruses. Nonetheless, the propensities and minimal components of BoDV-1 IBs 86 remain entirely elusive. 87 In this study, to clarify the mechanism of the formation of vSPOTs, we analyzed the 88 properties of the BoDV-1 N and P proteins from the aspect of phase-separated 89 condensates. We revealed that the BoDV-1 P protein alone causes LLPS in vitro, 90 depending on the intrinsically disordered region (IDR) present at the N-terminal region. 91 Although BoDV-1 N alone is not sufficient for the induction of LLPS, it was incorporated 92 into the BoDV-1 P droplets. Also, co-expression of BoDV-1 N and P is sufficient to induce 93 the formation of IB-like structures in cells. Further, P of BoDV-1, but not VSV or RSV, 94 binds to RNA. Interestingly, the N-terminal IDR of BoDV-1 P is involved in this RNA- 95 biding activity, which is overlapped with the region important for driving LLPS, while an 96 excess amount of RNA dissolved the liquid droplets consisting of BoDV-1 P alone and 97 BoDV-1 N and P. These findings are expected to help clarify the fundamental mechanism 5 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.24.445377; this version posted May 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 98 of the morphological regulation of the IBs of BoDV-1 and the comprehensive 99 mechanisms underlying the formation of biomolecular condensates. 100 101 Materials and methods 102 DNA constructs and antibodies 103 Escherichia coli expression vectors were constructed as follows. Oligonucleotides of 104 codon-optimized BoDV-1 N, P, His-tagged enhanced green fluorescent protein (EGFP), 105 and His-tagged mCherry (strain He/80/FR) were synthesized by Thermo Fisher Scientific 106 (Waltham, MA, USA). The synthesized oligonucleotides of BoDV-1 N and P were 107 inserted into the XhoI and BamHI restriction sites of the plasmid pET-15b using 108 NEBuilder HiFi DNA Assembly Master Mix (E2621; New England Bioscience, Ipswich, 109 MA, USA), which were designated as pET-15b-BoDV-1-Nco and pET-15b-BoDV-1-Pco, 110 respectively. The synthesized oligonucleotides of His-tagged mCherry and EGFP were 111 cloned into pET-15b using the NcoI and NdeI restriction sites, which were named pET- 112 15b-His-mCherry and pET-15b-His-EGFP, respectively.
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