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Alternative Capture of Noncoding RNAs or Protein-Coding Genes by Herpesviruses to Alter Host T-Cell Function

ABSTRACT: In marmoset T cells transformed by Herpesvirus saimiri (HVS), a viral U-rich noncoding RNA, HSUR 1, specifically mediates degradation of host microRNA-27 (miR-27). High-throughput sequencing of RNA after crosslinking immunoprecipitation (HITS-CLIP) identified mRNAs targeted by miR-27 as enriched in the T-cell receptor (TCR) signaling pathway, including GRB2. Accordingly, transfection of miR-27 into human T cells attenuates TCR-induced activation of mitogen-activated protein kinases (MAPKs) and induction of CD69. MiR-27 also robustly regulates SEMA7A and IFN-γ, key modulators and effectors of T-cell function. Knockdown or ectopic expression of HSUR 1 alters levels of these proteins in virally-transformed cells. Two other T-lymphotropic γ-herpesviruses, AlHV-1 and OvHV-2, do not produce a noncoding RNA to downregulate miR-27, but instead encode homologs of miR-27 target genes. Thus, oncogenic γ-herpesviruses have evolved diverse strategies to converge on common targets in host T cells.

ORGANISM(S): Callithrix jacchus

PROVIDER: GSE55185 | GEO | 2014/09/01

SECONDARY ACCESSION(S): PRJNA238829

REPOSITORIES: GEO

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Alternative Capture of Noncoding RNAs or Protein-Coding Genes by Herpesviruses to Alter Host T-Cell Function

Project description:In marmoset T cells transformed by Herpesvirus saimiri (HVS), a viral U-rich noncoding RNA, HSUR 1, specifically mediates degradation of host microRNA-27 (miR-27). High-throughput sequencing of RNA after crosslinking immunoprecipitation (HITS-CLIP) identified mRNAs targeted by miR-27 as enriched in the T-cell receptor (TCR) signaling pathway, including GRB2. Accordingly, transfection of miR-27 into human T cells attenuates TCR-induced activation of mitogen-activated protein kinases (MAPKs) and induction of CD69. MiR-27 also robustly regulates SEMA7A and IFN-γ, key modulators and effectors of T-cell function. Knockdown or ectopic expression of HSUR 1 alters levels of these proteins in virally-transformed cells. Two other T-lymphotropic γ-herpesviruses, AlHV-1 and OvHV-2, do not produce a noncoding RNA to downregulate miR-27, but instead encode homologs of miR-27 target genes. Thus, oncogenic γ-herpesviruses have evolved diverse strategies to converge on common targets in host T cells. HVS-transformed marmoset T cells were transfected with ASOs against HSUR 1 or control, or with LNAs against miR-27 or control, in replicates; poly A+ RNAs were selected and sequenced on HiSeq 2000.

2014-09-01 | E-GEOD-55185 | biostudies-arrayexpress

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2017-04-03 | GSE85587 | GEO

Expression data of ITK deficient, HVS transformed CD4+ T cells

Project description:We analyzed gene expression profiles of unstimulated Herpesvirus Saimiri (HVS) transformed T cells (CD4+) of patients harboring a homozygous R335W mutation in the IL-2 inducible T cell kinase (ITK) compared to healthy control HVS cells. We identified a set of 1927 Affymetrix probe sets showing significant misregulation in the ITK deficient cells (Welch's T-test, p<0.05).

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Expression data of ITK deficient, HVS transformed CD4+ T cells

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Project description:In latently-infected marmoset T cells, Herpesvirus saimiri (HVS) expresses six microRNAs (known as miR-HSURs). The viral miR-HSURs are processed from chimeric primary transcripts, each containing a noncoding U-rich RNA (HSUR) and a pre-miRNA hairpin. To uncover functions of miR-HSURs, we identified mRNA targets in infected cells using High-Throughput Sequencing of RNA Isolated by Crosslinking Immunoprecipitation (HITS-CLIP). HITS-CLIP revealed hundreds of robust Argonaute (Ago) binding sites mediated by miR-HSURs in the host genome, but few in the HVS genome. Gene Ontology analysis showed that several pathways regulating the cell cycle are enriched among cellular targets of miR-HSURs. Interestingly, miR-HSUR4-3p represses expression of the p300 transcriptional co-activator by binding the open reading frame of its mRNA. miR-HSUR5-3p directly regulates BiP, an endoplasmic reticulum (ER) localized chaperone facilitating maturation of the Major Histocompatibility Complex I (MHC I) and the antiviral response. miR-HSUR5-3p also robustly downregulates WEE1, a key negative regulator of cell-cycle progression, leading to reduced phosphorylation of its substrate cyclin-dependent kinase (Cdk1). Consistently, inhibition of miR-HSUR5-3p in HVS-infected cells decreases their proliferation. Together, our results shed light on the roles of viral miRNAs in cellular transformation and viral latency.

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Structural Basis for Target-Directed MicroRNA Degradation

Project description:We used HSUR1 – a small non-coding RNA from Herpesvirus saimiri that induces degradation of host miR-27 – to validate structural insights into target-directed miRNA degradation (TDMD). While performing systematic mutagenesis of HSUR1 we noticed that HSUR1 mutants exhibiting complementarity to the extreme 3' end of miR-27, lead to generation of extended miR-27 isoforms (isomiRs). These isomiRs likely represent failed products of TDMD and could mean that features of the pairing between the TDMD target and miRNA dictate which enzymes are recruited to modify the miRNA 3′ end. Small RNA sequencing revealed that a mixture of adenylates and uridylates is added to the 3′ end of miR-27 during TDMD.

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Project description:To check the gene signatures of SEMA7A high and SEMA7Anegative IPF lung fibroblasts and the similarity of SEMA7A high fibroblasts and invasive fibroblasts, SEMA7A negative fibroblasts and noninvasive fibroblasts, we sorted the SEMA7A high and negative IPF lung fibroblasts by flow cytometry and performed total RNA-seq.

2019-12-31 | GSE137025 | GEO

T cell activation decreases microRNA-15a/16 levels as a mechanism to promote MEK1-ERK1/2-Elk1 signaling for optimal proliferative capacity

Project description:While microRNAs (miRs) have been extensively studied in the context of malignancy and tumor progression, their functions in regulating T cell activation are less clear. We found reduced levels of miR-15a/16 at 3-18 h post-T cell receptor (TCR) stimulation, suggesting a role in shaping T cell activation. An inducible miR15a/16 transgenic mouse model was developed to determine how elevating miR-15a/16 levels during early stages of activation would affect T cell proliferation and to identify TCR signaling pathways regulated by this miR pair. Doxycyclin (DOX) induced expression of miR-15a/16 from 0-18 h post-TCR stimulation decreased ex vivo proliferation as well as in vivo antigen-specific proliferation. Bioinformatic and proteomic approaches were combined to identify MEK1 as a target of miR-15a/16. MEK1 targeting by miR-15a/16 was confirmed using miR mimics that decreased MEK1 containing the 3’-UTR target nucleotide sequence (UGCUGCUA) but did not decrease MEK1 containing a mutated control sequence (AAAAAAAA). Phosphorylation of downstream signaling molecules ERK1/2 and Elk1 were decreased with DOX-induced miR-15a/16 expression. In addition to MEK1, ERK1 was subsequently found to be targeted by miR-15a/16, with DOX induced miR-15a/16 reducing total ERK1 levels in T cells. These findings show that TCR stimulation reduces miR-15a/16 levels at early stages of T cell activation to facilitate increased MEK1 and ERK1, and this promotes sustained MEK1-ERK1/2-Elk1 signaling required for optimal proliferation.

2022-04-04 | PXD030935 | Pride

Identification of viral ncRNA-mRNA interactions in Herpesvirus saimiri-infected marmoset T cells

Project description:Viruses express several classes of non-coding (nc) RNAs1. For most of them, the functions and mechanisms by which they act are unknown. Herpesvirus saimiri (HVS), a g-herpesvirus that establishes latency in T cells of New World primates and has the ability to cause aggressive leukemias and lymphomas in non-natural hosts2, expresses seven small nuclear (sn), U-rich ncRNAs called HSURs in latently infected cells3-5. HSURs associate with Sm proteins and share biogenesis and structural features with cellular Sm-class snRNAs4,6. One of these viral snRNAs, HSUR 2, base-pairs with two host microRNAs (miRNAs), miR-142-3p and miR-167. However, HSUR 2 does not affect the abundance or activity of these two cellular miRNAs, suggesting alternative functions for these interactions. Here we show that HSUR 2 also base-pairs with messenger RNAs (mRNAs) in infected cells. We combined in vivo psoralen-mediated RNA-RNA crosslinking and high-throughput sequencing to identify mRNAs targeted by HSUR 2. HSUR 2 targets include mRNAs encoding Retinoblastoma (pRb) and factors involved in p53 signaling and apoptosis. We show that HSUR 2 represses expression of target mRNAs. Base-pairing between HSUR 2 and miR-142-3p and miR-16 is essential for HSUR 2-mediated mRNA repression, suggesting that HSUR 2 recruits these two cellular miRNAs to target mRNAs. Moreover, we show that HSUR 2 utilizes this mechanism to inhibit apoptosis. Our results uncover a role for a viral Sm-class RNA as a miRNA adaptor in post pre-mRNA-processing regulation of gene expression.

2017-10-01 | GSE79082 | GEO

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