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Unique Composition of Intronless and Intron-Containing Type I Ifns in The Unique Composition of Intronless and Intron-Containing Type I IFNs in the Tibetan Frog Nanorana parkeri Provides New Evidence To Support Independent This information is current as Retroposition Hypothesis for Type I IFN of September 28, 2021. Genes in Amphibians Zhen Gan, Yue Cong Yang, Shan Nan Chen, Jing Hou, Zubair Ahmed Laghari, Bei Huang, Nan Li and Pin Nie Downloaded from J Immunol published online 2 November 2018 http://www.jimmunol.org/content/early/2018/11/01/jimmun ol.1800553 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2018/11/01/jimmunol.180055 Material 3.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 2, 2018, doi:10.4049/jimmunol.1800553 The Journal of Immunology Unique Composition of Intronless and Intron-Containing Type I IFNs in the Tibetan Frog Nanorana parkeri Provides New Evidence To Support Independent Retroposition Hypothesis for Type I IFN Genes in Amphibians Zhen Gan,*,† Yue Cong Yang,*,† Shan Nan Chen,* Jing Hou,*,† Zubair Ahmed Laghari,* Bei Huang,* Nan Li,* and Pin Nie*,‡,x In vertebrates, intron-containing and intronless type I IFN genes have recently been reported in amphibian model species Xenopus tropicalis and X. laevis. However, whether intronless type I IFNs in amphibians are the ancestral genes of type I IFNs in amniotes or just represent the independent divergence in amphibians is unknown or even uninvestigated. In this study, both intron- Downloaded from containing and intronless type I IFN genes, as well as their receptor genes, were identified in the Tibetan frog Nanorana parkeri. The evidence obtained from homology, synteny, phylogeny, and divergence time showed that intronless type I IFN genes in N. parkeri and in Xenopus might have arisen from two independent retroposition events occurred in these two lineages, and the retrotransposition causing the generation of intronless type I IFN genes in amniotes is another independent event beyond the two in amphibians. It can then be proposed that intronless type I IFNs in N. parkeri and Xenopus may not be the ancestral genes of intronless type I IFNs in amniotes but may just represent two independent bifurcations in the amphibian lineage. Furthermore, http://www.jimmunol.org/ both intronless and intron-containing type I IFNs in N. parkeri showed strong ability in inducing the expression of IFN-stimulated genes and the strong antiviral activity against frog virus 3. The present study thus provides the evolutionary evidence to support the independent retroposition hypothesis for the occurrence of intronless type I IFN genes in amphibians and contributes to a functional understanding of type I IFNs in this group of vertebrates. The Journal of Immunology, 2018, 201: 000–000. nterferons are a family of pleiotropic cytokines with antivi- From an evolutionary point of view, type I IFNs have been ral, antitumor, and immunoregulatory functions in verte- identified in the classes of vertebrates from fish (teleost and car- brates (1–3). According to sequence similarity, receptor tilaginous fishes) to mammals (5, 6, 12–16). However, the detailed I by guest on September 28, 2021 usage, and biological activity, IFNs are currently classified into phylogeny and evolutionary history of type I IFNs have not been three types [i.e., type I, type II, and type III IFNs (1–3)], among fully elucidated in vertebrates. An obvious difference among type which type I IFNs are considered as quintessential antiviral cy- I IFNs in vertebrates is their gene organization: type I IFNs in fish tokines because of their central roles in antiviral immune response are encoded by intron-containing genes with the genomic orga- (1, 4). In mammals, type I IFNs have at least seven major ho- nization of five exons and four introns (12, 13), whereas type I IFN mologous subgroups, including multigene a subtype with 13 genes in mammals, birds, and reptiles are intronless and are members in human and a single gene of each b, ε, k, t, d, and v expressed as single-exon transcripts (5, 6, 14). How and when the subtypes (5, 6). A striking feature of type I IFN signaling in primitive intron-containing type I IFN genes might have lost their mammals is the high redundancy of ligands, and all type I IFN introns and evolved into intronless type I IFN genes in amniotes members initiate signaling via the interaction with the same het- can be an intriguing question in the field of evolutionary immu- erodimeric receptor complex composed of IFNAR1 and IFNAR2 nology (12). (7, 8), thus leading to the transcription of several hundred Retroposition is recognized as a RNA-based duplication for the IFN-stimulated genes (ISGs) (9–11). creation of intronless duplicate genes in new genomic positions *State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Address correspondence and reprint requests to Prof. Pin Nie, Institute of Hydro- Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei Province 430072, biology, Chinese Academy of Sciences, 7 South Donghu Road, Wuchang District, China; †University of Chinese Academy of Sciences, Beijing 100049, China; Wuhan, Hubei Province 430072, China. E-mail address: [email protected] ‡Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory The online version of this article contains supplemental material. for Marine Science and Technology, Qingdao, Shandong Province 266237, China; and xCollege of Marine Science and Engineering, Qingdao Agricultural University, Abbreviations used in this article: BI, Bayesian inference; CPE, cytopathic effect; Qingdao, Shandong Province 266109, China CRFB5, cytokine receptor family B–5; EPC, epithelioma papulosum cyprini; FNIII, fibronectin type III; FOCAD, focadhesin; FV3, frog virus 3; HA, hemagglutinin; ORCIDs: 0000-0003-0009-3051 (Y.C.Y.); 0000-0002-9492-2940 (P.N.). HACD4, 3-hydroxyacyl-CoA dehydratase 4; HEK293T, human embryonic kidney Received for publication April 18, 2018. Accepted for publication September 17, 293T; hpi, hour postinjection; IFIT-5, IFN-induced protein with tetratricopeptide 2018. repeats 5; ISG, IFN-stimulated gene; ML, maximum likelihood; MYA, million years ago; NCBI, National Center for Biotechnology Information; NJ, neighbor-joining; This work was supported by a grant (31230075) from the National Natural Science Np-IFNAR1, predicted IFNAR1 in N. parkeri; ORF, open reading frame; pcDNA3.1, Foundation of China, by the China Agriculture Research System (CARS-46), and by pcDNA3.1/myc-His (2) A vector; pcDNA3.1–Np-IFN1, Np-IFN1 subcloned into special top talent plan One Thing One Decision (Yishi Yiyi) in Shandong Province, pcDNA3.1; pcDNA3.1–Np-IFNAR1, Np-IFNAR1 subcloned into pcDNA3.1; poly(I:C), China. polyinosinic/polycytidylic acid; rNp-IFN, recombinant Np-IFN. The sequences presented in this article have been submitted to the National Center for Biotechnology Information’s GenBank database (https://ncbi.nlm.nih.gov/genbank/) un- Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$37.50 der accession numbers MG999514, MF346696, MG999515, MG999516, and MG999517. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800553 2 TIBETAN FROG TYPE I IFNs through the reverse transcription of parental genes (17). In a Fisher Scientific) to extract total RNA with TRIzol (Invitrogen). To analyze previous study to explore the possible molecular mechanism in the the expression of genes in N. parkeri after stimulation, 12 healthy individuals m generation of intronless type I IFNs, a hypothesis was proposed were each injected i.p. with polyinosinic/polycytidylic acid [poly(I:C);10 g/g body weight; Sigma-Aldrich] dissolved in amphibian PBS (pH 7.2) (21) and that intronless type I IFN genes in amniotes might have arisen were divided into four groups, each with three individuals. Twelve healthy from primitive intron-containing type I IFN genes via a retro- individuals as control were injected i.p. with an equal volume of amphibian position event when vertebrates migrated from aquatic to terres- PBS and were also equally divided into four groups. At 3, 6, 12, and 24 h trial environments (18). Now, this hypothesis has been generally postinjection (hpi), three animals in each group were sacrificed for the collection of organs/tissues, which were then placed in RNAlater (Thermo accepted (19, 20), but when this retroposition event might have Fisher Scientific) for extracting RNA with TRIzol. In addition, the muscle happened still remains unknown or uninvestigated. of healthy N. parkeri was taken and stored in ethanol for isolating the Interestingly, it is recently revealed that intronless and intron- genomic DNA. All animal protocols were performed following the Guide containing type I IFN
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