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1 N 6-Methyladenosine of HIV-1 RNA Regulates Viral Infection And 1 N6-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein 2 expression 3 4 Nagaraja Tirumuru1, #, Boxuan Simen Zhao2, 3, #, Wuxun Lu1, Zhike Lu2, 3, Chuan He2, 3, *, 5 Li Wu1, 4, 5, * 6 7 1 Center for Retrovirus Research, Department of Veterinary Biosciences, 4 Department of 8 Microbial Infection and Immunity, and 5 Comprehensive Cancer Center, The Ohio State 9 University, Columbus, Ohio 43210, USA. 10 11 2 Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for 12 Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, USA; 3 Howard 13 Hughes Medical Institute, The University of Chicago, Chicago, Illinois 60637, USA. 14 15 # These authors contributed equally. 16 17 * Corresponding authors 18 LW: [email protected], Phone: (614)-292-5408 19 CH: [email protected], Phone: (773)-702-5061 20 21 Competing interests statement: The authors declare that no competing interests exist. 22 1 23 Abstract 24 25 The internal N6-methyladenosine (m6A) methylation of eukaryotic nuclear RNA controls 26 post-transcriptional gene expression, which is regulated by methyltransferases (writers), 27 demethylases (erasers), and m6A-binding proteins (readers) in cells. The YTH domain family 28 proteins (YTHDF1–3) bind to m6A-modified cellular RNAs and affect RNA metabolism and 29 processing. Here we show that YTHDF1–3 proteins recognize m6A-modified HIV-1 RNA and 30 inhibit HIV-1 infection in cell lines and primary CD4+ T-cells. We further mapped the 31 YTHDF1–3 binding sites in HIV-1 RNA from infected cells. We found that overexpression of 32 YTHDF proteins in cells inhibited HIV-1 infection mainly by decreasing HIV-1 reverse 33 transcription, while knockdown of YTHDF1–3 in cells had the opposite effects. Moreover, 34 silencing the m6A writers decreased HIV-1 Gag protein expression in virus-producer cells, while 35 silencing the m6A erasers increased Gag expression. Our findings suggest an important role of 36 m6A modification of HIV-1 RNA in viral infection and HIV-1 protein synthesis. 2 37 Introduction 38 Interactions of host proteins with HIV-1 substantially modulate viral replication and 39 pathogenesis (Goff, 2007; Moir et al., 2011). Host proteins that interact with HIV-1 nucleic acids 40 or viral proteins can either enhance or inhibit viral replication in cells. The secondary structure 41 model of HIV-1 RNA and its interactions with viral proteins have been recently analyzed 42 (Kutluay et al., 2014; Lavender et al., 2015; Watts et al., 2009; Wilkinson et al., 2008); however, 43 it is less clear whether host proteins can post-transcriptionally modify HIV-1 RNA, which may 44 affect interactions between RNA and host or viral proteins, thereby affecting HIV-1 infection. 45 N6-methyladenosine (m6A) is the most prevalent internal messenger RNA (mRNA) 46 modification in eukaryotic organisms and plays pivotal roles in post-transcriptional regulation of 47 gene expression (Fu et al., 2014; Jia et al., 2013; Yue et al., 2015). This methylation is reversible 48 (Jia et al., 2011; Zheng et al., 2013) and is specifically recognized by a family of reader proteins 49 (Liu et al., 2014; Wang et al., 2015). The m6A modification is widely distributed in mammalian 50 mRNAs, enriched in the 3’ untranslated region (UTR) near the stop codon and also present in the 51 5’ UTR and long exons (Dominissini et al., 2012; Meyer et al., 2012; Zhou et al., 2015). It has 52 been known for almost 40 years that RNAs of influenza virus, adenovirus, Rous sarcoma virus, 53 and simian virus 40 are m6A-methylated (Beemon and Keith, 1977; Canaani et al., 1979; 54 Hashimoto and Green, 1976; Krug et al., 1976), although the impact of the m6A modification on 55 viral replication remains unclear. Recent studies revealed that the m6A modification of HIV-1 56 RNA significantly affects viral replication and gene expression (Kennedy et al., 2016; Lichinchi 57 et al., 2016). Lichinchi et al. reported that HIV-1 mRNA contains multiple m6A modifications 58 and viral infection in a CD4+ T-cell line increases the m6A levels in both host and viral mRNAs 59 (Lichinchi et al., 2016), suggesting a dynamic regulation of m6A methylomes during HIV-1 3 60 infection. In contrast, Kennedy et al. only found four clusters of m6A modifications in the 3’ 61 UTR region of the HIV-1 RNA genome that enhance viral gene expression (Kennedy et al., 62 2016). 63 The dynamic addition, removal, and recognition of m6A in cellular mRNAs and other 64 types of nuclear RNAs are coordinately regulated by three groups of host proteins, including 65 adenosine methyltransferases (writers), m6A demethylases (erasers), and m6A-selective-binding 66 proteins (readers) (Fu et al., 2014). The methyltransferase complex is composed of METTL3, 67 METTL14 and WTAP (Wilms’ tumor 1-associating protein), which add m6A modification to 68 nuclear RNAs (Liu et al., 2014; Ping et al., 2014). The RNA demethylases FTO (fat mass and 69 obesity-associated protein) and AlkBH5 (AlkB family member 5) remove m6A modification of 70 RNAs (Fu et al., 2014; Jia et al., 2011). Three host proteins, including YTHDF1, 2, and 3 71 (YTHDF1–3), have been identified as selective m6A-binding proteins (readers) in mammalian 72 cells (Dominissini et al., 2012; Wang et al., 2014; Wang et al., 2015). These m6A-reader proteins 73 preferentially bind methylated mRNAs and control the stability and translation of target mRNAs 74 (Dominissini et al., 2012; Liu et al., 2014). Human YTHDF1–3 proteins contain a conserved 75 YTH RNA-binding domain that preferentially binds the m6A-containing RNAs and a P/Q/N-rich 76 region that is associated with different RNA-protein complexes (Fu et al., 2014). Lichinchi et al. 77 recently reported that silencing of the m6A writers or the eraser AlkBH5 decreases or increases 78 HIV-1 replication, respectively (Lichinchi et al., 2016). Kennedy et al. showed that m6A 79 modifications in the 3’ UTR region of HIV-1 RNA enhance viral gene expression by recruiting 80 cellular YTHDF proteins (Kennedy et al., 2016). However, neither study examined m6A 81 modification of HIV-1 RNA and its effect on HIV-1 replication in primary CD4+ T-cells, nor 82 systemically analyzed the role of the m6A writers, erasers, and readers in HIV-1 replication. 4 83 Here we show that HIV-1 RNA contains multiple m6A modifications enriched in the 5' 84 and 3' UTRs and within several coding genes. We mapped the specific sites in HIV-1 RNA 85 bound by YTHDF proteins in HIV-1-infected cells. We found that overexpression of YTHDF 86 proteins in target cells significantly inhibited HIV-1 infection, while knockdown of these 87 proteins in primary CD4+ T-cells enhanced HIV-1 infection. Furthermore, knockdown of the 88 m6A writers or the erasers decreased or increased HIV-1 Gag synthesis and virion release in 89 virus producer cells, respectively. Our findings suggest important functions of the m6A reader, 90 writer, and eraser proteins in modulating HIV-1 gene expression and viral infection through the 91 m6A modification of HIV-1 RNA. 92 93 Results 94 HIV-1 RNA genome contains m6A modifications. To investigate the presence of m6A 95 in HIV-1 RNA and to map the m6A modification within HIV-1 RNA, we isolated RNA samples 96 from CD4+ Jurkat T-cells or primary CD4+ T-cells infected with replication-competent HIV- 6 97 1NL4-3, and performed immunoprecipitation (IP) with poly(A)-enriched RNA using m A-specific 98 antibodies, followed by high-throughput RNA sequencing (m6A-seq) (Dominissini et al., 2012). 99 We identified similar profiles of m6A peaks in HIV-1 RNA from these two cell types, which are 100 mainly enriched in the 5' and 3' UTRs as well as the rev and gag genes of the HIV-1 genome 101 (Figure 1A, 1B). To confirm m6A modification of HIV-1 RNA from virus producer cells, we 102 transfected HEK293T cells with a plasmid containing full-length HIV-1 proviral DNA (pNL4-3) 103 and extracted total RNA from the transfected cells. Using the same m6A-seq approach, we 104 identified multiple m6A peaks in HIV-1 RNA, which are enriched in the 5' and 3' UTRs and 105 within overlapped HIV-1 coding genes, such as tat, rev, env, and nef (Figure 1–figure 5 106 supplement 1). These results confirm the m6A modification of HIV-1 RNA despite some 107 differences in m6A distributions in HIV-1 infected CD4+ T-cells compared to transfected 108 HEK293T cells. 109 To investigate whether HIV-1 virion RNA contains m6A, we isolated HIV-1 RNA from 110 highly purified HIV-1 virions derived from infected CD4+ T-cells (Rossio et al., 1998; Wang et 111 al., 2008), and then performed a quantitative analysis of m6A level using liquid chromatography- 112 mass spectrometry (Jia et al., 2011). Our data showed that m6A in HIV-1 RNA was 113 approximately 0.1% of total adenosines (Figure 1–figure supplement 2). Considering 35.8% of 114 HIV-1 genomic RNA (gRNA) (9,173 nucleotides) are adenosines (van Hemert et al., 2014), our 115 data suggest approximately 3-4 sites of the m6A modification in each copy of HIV-1 gRNA, 116 which match the numbers of m6A peaks identified by m6A-seq (Figure 1A, 1B and Figure 1– 117 figure supplement 1). Together, these results confirm that HIV-1 RNA contains m6A 118 modifications at multiple sites within the viral genome. 119 Distribution of m6A in the cellular RNAs and gene ontology (GO) analysis of m6A- 120 modified cellular genes. To examine the effect of HIV-1 infection on m6A modifications of 121 cellular RNAs, we compared the distribution of m6A peaks in cellular RNAs from HIV-1 122 infected and uninfected T-cells.
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