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RBM39 Alters Phosphorylation of C-Jun and Binds to Viral RNA To bioRxiv preprint doi: https://doi.org/10.1101/2020.11.13.382531; this version posted November 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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-ND 4.0 International license. 1 RBM39 alters phosphorylation of c-Jun and binds to viral RNA to 2 promote PRRSV proliferation 3 4 Running title: RBM39 promotes PRRSV proliferation 5 6 Yinna Song1#, Yanyu Guo1#, Xiaoyang Li1, Ruiqi Sun1, Min Zhu1, Jingxuan Shi1, Lilin 7 Zhang1,2,Jinhai Huang1,2* 8 9 1，School of Life Sciences, Tianjin University, Tianjin, China, 300072 10 2, Tianjin Key Laboratory of Function and Application of Biological Macromolecular 11 Structures, Tianjin University, Tianjin, China 12 13 14 *Corresponding author. 15 Mailing address: School of Life Science, Tianjin University, Tianjin 300072, China. No. 92, 16 Weijin road, Nankai District, Tianjin, 300072, China 17 Phone and Fax: 86-22-8740 2171, E-mail: [email protected] 18 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.13.382531; this version posted November 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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-ND 4.0 International license. 19 ABTRAST 20 As transcriptional co-activator of AP-1/Jun, estrogen receptors and NF-κB, 21 nuclear protein RBM39 also involves in precursor mRNA (pre-mRNA) splicing. 22 Porcine reproductive and respiratory syndrome virus (PRRSV) causes sow 23 reproductive disorders and piglet respiratory diseases, which resulted in serious 24 economic losses worldwide. In this study, the up-regulated expression of RBM39 and 25 down-regulated of inflammatory cytokines (TNF, IL-1β) were determined in 26 PRRSV-infected 3D4/21 cells, and accompanied with the PRRSV proliferation. The 27 roles of RBM39 altering phosphorylation of c-Jun to inhibit the AP-1 pathway to 28 promote PRRSV proliferation were further verified. In addition, the 29 nucleocytoplasmic translocation of RBM39 and c-Jun from nucleus to cytoplasm 30 were enhanced in PRRSV-infected cells. The three RRM domain of RBM39 are 31 crucial to support the proliferation of PRRSV. several PRRSV RNA (nsp4, nsp5, 32 nsp11 and N) binding with RBM39 were determined, which may also contribute to 33 the PRRSV proliferation. Our results revealed a complex mechanism of RBM39 by 34 altering c-Jun phosphorylation and nucleocytoplasmic translocation, and regulating 35 binding of RBM39 with viral RNA to prompt PRRSV proliferation. The results 36 provide new viewpoints to understand the immune escape mechanism of PRRSV 37 infection. 38 39 Key Words: RBM39, c-Jun, Porcine reproductive and respiratory syndrome virus, 40 AP-1, phosphorylation, interfein bioRxiv preprint doi: https://doi.org/10.1101/2020.11.13.382531; this version posted November 14, 2020. 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-ND 4.0 International license. 41 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.13.382531; this version posted November 14, 2020. 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-ND 4.0 International license. 42 Introduction 43 RNA-binding proteins (RBPs) have been found in all living organisms(1). 44 Through binding RNAs, RBPs assemble in ribonucleoprotein complexes, which 45 dictate the fate and the function of virtually every cellular RNA molecules. 46 RNA-binding proteins (RBPs) can bind single-stranded or double-stranded RNAs, 47 and play an important role in regulating RNA metabolism and gene expression as 48 post-transcriptional regulators(2). RBPs are involved in biological processes such as 49 RNA transcription, editing, splicing, transportation and positioning, stability and 50 translation(3). With the extensive reports on the post-transcriptional regulatory 51 mechanism of RNA-binding proteins, more and more scholars are focusing on their 52 functions. The target RNA of RBPs is variable, they can bind to different region of 53 mRNA [such as exons, introns, untranslated regions (UTRs)], or interact with other 54 types of RNA, including non-coding RNAs(4), microRNAs, small interference RNAs 55 (siRNA), t-RNAs, small nucleolar RNA (snoR-NA), telomerase RNA, conjugant 56 small nuclear RNA (snRNA) and the RNA part of signal recognition particles (SRP 57 RNA or 7SL RNA(5-7). These non-coding RNAs form a wide range of secondary 58 structures, which combine with RBP and regulate processes such as RNA splicing, 59 RNA modification(8), protein localization, translation, and maintenance of 60 chromosome stability(9, 10). The functional effects of conventional RBPs depend on 61 the target RNA-RNP complex formation. Simultaneously, the RNP complex helps 62 RNA processing, translation, export and localization(10, 11). 63 RBM39 (RNA binding motif protein 39), also called CAPER, HCC1.3/1.4、 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.13.382531; this version posted November 14, 2020. 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-ND 4.0 International license. 64 Caperα、FSAP59、RNPC2(12), is a nuclear protein that is involved in precursor 65 mRNA (pre-mRNA) splicing(13). RBM39 was first identified as an auto-antigen in a 66 hepatocellular carcinoma patient(14). In addition, RBM39 is a transcriptional 67 co-activator of activating protein-1 (AP-1/Jun) and estrogen receptors (eg, steroid 68 nuclear receptors ESR1/ER-alpha and ESR2/ER- β) and NF-κB(13, 15), and its 69 function has been associated with malignant progression in a number of cancers(14). 70 Previous studies have reported RBM39 as a proto-oncogene with important roles in 71 the development and progression of multiple types of malignancies(16). RBM39 is 72 relevant to numerous precursor messenger RNA (pre-mRNA) splicing factors and 73 RNA binding proteins. As a mRNA splicing factor, RBM39 provide regulating action 74 of a quantity of signal pathway(17). Degradation of RBM39 can led to aberrant 75 pre-mRNA splicing, including intron retention and exon skipping, in hundreds of 76 gene(14). RBM39 is extremely homologous and conserved in many species (Fig. 1B). 77 RBM39 has three RRM (RNA recognition motif) domains and the C-terminal of 78 RRM3 domain belongs to the U2AF homology motif family (UHM), which mediate 79 protein–protein interactions through a short tryptophan-containing peptide known as 80 the UHM-ligand motif (ULM). However, RBM39 impacting virus proliferation and 81 its role in innate immunity are largely unknown. 82 The activation protein-1 (AP-1) transcription factors are immediate early 83 response genes involved in a diverse set of transcriptional regulatory processes(18, 84 19). The AP-1 complex consists of a heterodimer of a Fos family member and a Jun 85 family member(20). The Fos family contains four proteins (c-Fos, Fos-B, Fra-1, and bioRxiv preprint doi: https://doi.org/10.1101/2020.11.13.382531; this version posted November 14, 2020. 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-ND 4.0 International license. 86 Fra-2), whereas the Jun family is composed of three proteins (c-Jun, Jun-B, and 87 Jun-D)(18). The c-Jun is a central component of all AP-1 complexes and members of 88 the basic region-leucine zipper (bZIP) family of sequence-specific dimeric 89 DNA-binding proteins. In addition, the c-Jun is a transcription factor that recognizes 90 and AP-1 complex binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3' (termed 91 AP-1 sites) found in a variety of promoters(13, 18). The c-Jun gene is expressed in 92 many cell types at low levels, and its expression is in elevated response to many 93 stimuli, including growth factors, cytokines, foreign materials and viral infection. 94 Some stimuli of cells result in activation of the JNK (c-Jun N-terminal kinase) and 95 p38 groups of MAPKs(8). The c-Jun were phosphorylated at two positive regulatory 96 sites (serine 63 and 73) residing within its amino-terminal activation domain by 97 JNKs(18). 98 Porcine reproductive and respiratory syndrome virus (PRRSV) is a critical 99 pathogen in pig and can trigger a serious negative impact on the economic 100 development of pigs(21), which mainly causes sow reproductive disorders and piglets 101 respiratory diseases, thus resulting in serious economic losses in the world(22). It is a 102 variety of capsule single-stranded positive-chain virus of arteritis virus(23). Infections 103 by PRRSV often result in increased expression of multiple genes and delayed, 104 low-level induction of antiviral cytokines, thereby destroying the early endogenous 105 immune response(24). The 15kb PRRSV genome is expressed through a set of 106 subgenomic mRNA transcripts,each used for the translation of one or two open 107 reading frames (ORFs)(25, 26). The full-length viral RNA is used for the translation bioRxiv preprint doi: https://doi.org/10.1101/2020.11.13.382531; this version posted November 14, 2020.
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