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Dynamic nature of noncoding RNA regulation of adaptive immune response.

Curtale G, Citarella F - Int J Mol Sci (2013)

Bottom Line: Immune response plays a fundamental role in protecting the organism from infections; however, dysregulation often occurs and can be detrimental for the organism, leading to a variety of immune-mediated diseases.Recently our understanding of the molecular and cellular networks regulating the immune response, and, in particular, adaptive immunity, has improved dramatically.For many years, much of the focus has been on the study of protein regulators; nevertheless, recent evidence points to a fundamental role for specific classes of noncoding RNAs (ncRNAs) in regulating development, activation and homeostasis of the immune system.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biotechnologies and Translational Medicine, University of Milan, Rozzano 20089, Italy. graziella.curtale@humanitasresearch.it

ABSTRACT
Immune response plays a fundamental role in protecting the organism from infections; however, dysregulation often occurs and can be detrimental for the organism, leading to a variety of immune-mediated diseases. Recently our understanding of the molecular and cellular networks regulating the immune response, and, in particular, adaptive immunity, has improved dramatically. For many years, much of the focus has been on the study of protein regulators; nevertheless, recent evidence points to a fundamental role for specific classes of noncoding RNAs (ncRNAs) in regulating development, activation and homeostasis of the immune system. Although microRNAs (miRNAs) are the most comprehensive and well-studied, a number of reports suggest the exciting possibility that long ncRNAs (lncRNAs) could mediate host response and immune function. Finally, evidence is also accumulating that suggests a role for miRNAs and other small ncRNAs in autocrine, paracrine and exocrine signaling events, thus highlighting an elaborate network of regulatory interactions mediated by different classes of ncRNAs during immune response. This review will explore the multifaceted roles of ncRNAs in the adaptive immune response. In particular, we will focus on the well-established role of miRNAs and on the emerging role of lncRNAs and circulating ncRNAs, which all make indispensable contributions to the understanding of the multilayered modulation of the adaptive immune response.

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Key steps in microRNA (miRNA) biogenesis and activity. miRNAs originate from the nucleus as pri-miRNA precursor molecules, organized as single transcriptional units or as a cluster of miRNAs, co-transcribed as a polycistronic transcript. They are processed by the RNAse III-type enzyme, Drosha, in association with the RNA-binding protein, DGCR8, into smaller precursor miRNAs (pre-miRNAs), then exported to cytoplasm, where they are cleaved by Dicer to their mature form of 22 nt double stranded miRNA. The guide strand of the mature miRNA is incorporated into the miRNA-induced silencing complex (miRISC), where it binds to target mRNA by partial complementarity with its 3′UTR. This results in translational inhibition, mRNA degradation or mRNA deadenylation of the recognized miRNA target. Ago, Argonaute.
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f1-ijms-14-17347: Key steps in microRNA (miRNA) biogenesis and activity. miRNAs originate from the nucleus as pri-miRNA precursor molecules, organized as single transcriptional units or as a cluster of miRNAs, co-transcribed as a polycistronic transcript. They are processed by the RNAse III-type enzyme, Drosha, in association with the RNA-binding protein, DGCR8, into smaller precursor miRNAs (pre-miRNAs), then exported to cytoplasm, where they are cleaved by Dicer to their mature form of 22 nt double stranded miRNA. The guide strand of the mature miRNA is incorporated into the miRNA-induced silencing complex (miRISC), where it binds to target mRNA by partial complementarity with its 3′UTR. This results in translational inhibition, mRNA degradation or mRNA deadenylation of the recognized miRNA target. Ago, Argonaute.

Mentions: miRNAs are small, single-stranded endogenous ncRNAs, of about 22 nucleotides (nt), many of which are highly conserved through evolution. They are encoded by genes that produce transcripts for either single or multiple miRNAs or by intronic sequences of protein coding genes. Their expression is highly regulated and can be tissue- and time-specific. Following transcription, the primary RNA transcripts (pri-miRNAs), which form a distinctive hairpin structure, are processed by a complex formed by ribonuclease III-type Drosha and DiGeorge syndrome critical region gene 8 (Drosha/DGCR8) and, then, exported from the nucleus into the cytoplasm as pre-miRNA [21]. In the cytoplasm, pre-miRNAs are recognized and cleaved by another endoribonuclease, Dicer, which generates a 22 nt double-stranded miRNA. The double stranded miRNA is unwound, and one strand, the guide strand, is loaded into the RNA-induced silencing complex (RISC). Within the RISC, the mature miRNA interacts with Argonaute (Ago) proteins, driving Ago and other associated factors to partially complementary target sites, mainly located in the 3′ UTR (3′ untranslated region) of the target messenger RNAs (mRNAs) [21–23]. The resulting effect of miRNA-target mRNA interaction inside the RISC complex is the translational inhibition, degradation or deadenylation of the target mRNAs [24,25] (Figure 1).


Dynamic nature of noncoding RNA regulation of adaptive immune response.

Curtale G, Citarella F - Int J Mol Sci (2013)

Key steps in microRNA (miRNA) biogenesis and activity. miRNAs originate from the nucleus as pri-miRNA precursor molecules, organized as single transcriptional units or as a cluster of miRNAs, co-transcribed as a polycistronic transcript. They are processed by the RNAse III-type enzyme, Drosha, in association with the RNA-binding protein, DGCR8, into smaller precursor miRNAs (pre-miRNAs), then exported to cytoplasm, where they are cleaved by Dicer to their mature form of 22 nt double stranded miRNA. The guide strand of the mature miRNA is incorporated into the miRNA-induced silencing complex (miRISC), where it binds to target mRNA by partial complementarity with its 3′UTR. This results in translational inhibition, mRNA degradation or mRNA deadenylation of the recognized miRNA target. Ago, Argonaute.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3794731&req=5

f1-ijms-14-17347: Key steps in microRNA (miRNA) biogenesis and activity. miRNAs originate from the nucleus as pri-miRNA precursor molecules, organized as single transcriptional units or as a cluster of miRNAs, co-transcribed as a polycistronic transcript. They are processed by the RNAse III-type enzyme, Drosha, in association with the RNA-binding protein, DGCR8, into smaller precursor miRNAs (pre-miRNAs), then exported to cytoplasm, where they are cleaved by Dicer to their mature form of 22 nt double stranded miRNA. The guide strand of the mature miRNA is incorporated into the miRNA-induced silencing complex (miRISC), where it binds to target mRNA by partial complementarity with its 3′UTR. This results in translational inhibition, mRNA degradation or mRNA deadenylation of the recognized miRNA target. Ago, Argonaute.
Mentions: miRNAs are small, single-stranded endogenous ncRNAs, of about 22 nucleotides (nt), many of which are highly conserved through evolution. They are encoded by genes that produce transcripts for either single or multiple miRNAs or by intronic sequences of protein coding genes. Their expression is highly regulated and can be tissue- and time-specific. Following transcription, the primary RNA transcripts (pri-miRNAs), which form a distinctive hairpin structure, are processed by a complex formed by ribonuclease III-type Drosha and DiGeorge syndrome critical region gene 8 (Drosha/DGCR8) and, then, exported from the nucleus into the cytoplasm as pre-miRNA [21]. In the cytoplasm, pre-miRNAs are recognized and cleaved by another endoribonuclease, Dicer, which generates a 22 nt double-stranded miRNA. The double stranded miRNA is unwound, and one strand, the guide strand, is loaded into the RNA-induced silencing complex (RISC). Within the RISC, the mature miRNA interacts with Argonaute (Ago) proteins, driving Ago and other associated factors to partially complementary target sites, mainly located in the 3′ UTR (3′ untranslated region) of the target messenger RNAs (mRNAs) [21–23]. The resulting effect of miRNA-target mRNA interaction inside the RISC complex is the translational inhibition, degradation or deadenylation of the target mRNAs [24,25] (Figure 1).

Bottom Line: Immune response plays a fundamental role in protecting the organism from infections; however, dysregulation often occurs and can be detrimental for the organism, leading to a variety of immune-mediated diseases.Recently our understanding of the molecular and cellular networks regulating the immune response, and, in particular, adaptive immunity, has improved dramatically.For many years, much of the focus has been on the study of protein regulators; nevertheless, recent evidence points to a fundamental role for specific classes of noncoding RNAs (ncRNAs) in regulating development, activation and homeostasis of the immune system.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biotechnologies and Translational Medicine, University of Milan, Rozzano 20089, Italy. graziella.curtale@humanitasresearch.it

ABSTRACT
Immune response plays a fundamental role in protecting the organism from infections; however, dysregulation often occurs and can be detrimental for the organism, leading to a variety of immune-mediated diseases. Recently our understanding of the molecular and cellular networks regulating the immune response, and, in particular, adaptive immunity, has improved dramatically. For many years, much of the focus has been on the study of protein regulators; nevertheless, recent evidence points to a fundamental role for specific classes of noncoding RNAs (ncRNAs) in regulating development, activation and homeostasis of the immune system. Although microRNAs (miRNAs) are the most comprehensive and well-studied, a number of reports suggest the exciting possibility that long ncRNAs (lncRNAs) could mediate host response and immune function. Finally, evidence is also accumulating that suggests a role for miRNAs and other small ncRNAs in autocrine, paracrine and exocrine signaling events, thus highlighting an elaborate network of regulatory interactions mediated by different classes of ncRNAs during immune response. This review will explore the multifaceted roles of ncRNAs in the adaptive immune response. In particular, we will focus on the well-established role of miRNAs and on the emerging role of lncRNAs and circulating ncRNAs, which all make indispensable contributions to the understanding of the multilayered modulation of the adaptive immune response.

Show MeSH
Related in: MedlinePlus