Eri1 regulates microRNA homeostasis and mouse lymphocyte development and antiviral function

Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Blood (Impact Factor: 10.45). 05/2012; 120(1):130-42. DOI: 10.1182/blood-2011-11-394072
Source: PubMed


Natural killer (NK) cells play a critical role in early host defense to infected and transformed cells. Here, we show that mice deficient in Eri1, a conserved 3'-to-5' exoribonuclease that represses RNA interference, have a cell-intrinsic defect in NK-cell development and maturation. Eri1(-/-) NK cells displayed delayed acquisition of Ly49 receptors in the bone marrow (BM) and a selective reduction in Ly49D and Ly49H activating receptors in the periphery. Eri1 was required for immune-mediated control of mouse CMV (MCMV) infection. Ly49H(+) NK cells deficient in Eri1 failed to expand efficiently during MCMV infection, and virus-specific responses were also diminished among Eri1(-/-) T cells. We identified miRNAs as the major endogenous small RNA target of Eri1 in mouse lymphocytes. Both NK and T cells deficient in Eri1 displayed a global, sequence-independent increase in miRNA abundance. Ectopic Eri1 expression rescued defective miRNA expression in mature Eri1(-/-) T cells. Thus, mouse Eri1 regulates miRNA homeostasis in lymphocytes and is required for normal NK-cell development and antiviral immunity.

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Available from: Sarah Abdul-Wajid, Dec 01, 2015
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    • "Another study by Thomas et al. (2012) focused on Eri1, an exoribonuclease that degrades miRNAs and thus functions as a negative regulator of miRNA-mediated control, and the effects of its loss on NK and T cells. The authors found that Eri1-deficient NK and T cells displayed an increase in total miRNA abundance. "
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    ABSTRACT: Natural killer (NK) cells are innate immune lymphocytes critical for host defense against viral infection and surveillance against malignant transformation. MicroRNAs (miRNAs) are a family of small, non-coding RNAs that regulate a wide variety of cellular processes. Recent advances have highlighted the importance of miRNA-mediated post-transcriptional regulation in NK cell development, maturation, and function. This review focuses on several facets of this regulatory mechanism in NK cells: (1) the expressed NK cell miRNA transcriptome; (2) the impact of total miRNA deficiency on NK cells; (3) the role of specific miRNAs regulating NK cell development, survival, and maturation; (4) the intrinsic role of miRNAs regulating NK cell function, including cytokine production, proliferation, and cytotoxicity; and (5) the role of NK cell miRNAs in disease. Currently our knowledge of how miRNAs regulate NK cell biology is limited, and thus we also explore key open questions in the field, as well as approaches and techniques to ascertain the role of individual miRNAs as important molecular regulators.
    Full-text · Article · Feb 2013 · Frontiers in Immunology
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    • "Consequently, both miR-221 overexpression and knockdown of hPNPaseold-35 protect human melanoma cells from INF-β- induced growth arrest, indicating a pivotal role of controlled miRNA decay in tuning cell proliferation [199]. The 3′–5′ exoribonuclease Eri1 was recently implicated in regulating miRNA stability in mouse lymphocytes, based on the global increase in miRNA levels observed in NK and T cells from Eri1 knockout mice [200]. The regulation of miRNA levels by Eri1 appears to be required for NK-cell development and antiviral immunity, but its mechanism of action remains to be established. "
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    ABSTRACT: MicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes.
    Full-text · Article · Jan 2013 · Cellular and Molecular Life Sciences CMLS
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    • "Another study by Thomas et al. [40] focused on Eri1, a highly conserved exoribonuclease that is involved in 5.8S rRNA 3′ end processing and a negative regulator of global miRNA abundance. The authors found that Eri1-deficient NK and T cells displayed an increase in global miRNA abundance. "
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    ABSTRACT: Natural killer (NK) cells are innate immune lymphocytes that are critical for normal host defense against infections and mediate antitumor immune responses. MicroRNAs (miRNAs) are a family of small, noncoding RNAs that posttranscriptionally regulate the majority of cellular processes and pathways. Our understanding of how miRNAs regulate NK cells biology is limited, but recent studies have provided novel insight into their expression by NK cells, and how they contribute to the regulation of NK cell development, maturation, survival, and effector function. Here, we review the expression of miRNAs by NK cells, their contribution to cell intrinsic and extrinsic control of NK cell development and effector response, and their dysregulation in NK cell malignancies.
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