CRM1 mediates nuclear-cytoplasmic shuttling of mature microRNAs

Castanotto, Daniela; Lingeman, Robert; Riggs, Arthur D.; Rossi, John J.

doi:10.1073/pnas.0912384106

Cited by 103 publications

(106 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies showed that Exportin-1, an essential transport factor for certain proteins and RNAs, supports pri-miRNA processing in Caenorhabditis elegans and Drosophila, as well as shuttling of mature miRNA from the cytoplasm to the nucleus (28,41,42). Recently, we showed that Exportin-1 is involved in the nuclear export of a group of mammalian (m 7 G)-capped pre-miRNAs in proliferating cells (27).…”

Section: Exportin-1 Is Required For Processing Of Quiescence-induced mentioning

confidence: 99%

An Exportin-1–dependent microRNA biogenesis pathway during human cell quiescence

Martínez

Hayes

Barr

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The reversible state of proliferative arrest known as "cellular quiescence" plays an important role in tissue homeostasis and stem cell biology. By analyzing the expression of miRNAs and miRNAprocessing factors during quiescence in primary human fibroblasts, we identified a group of miRNAs that are induced during quiescence despite markedly reduced expression of Exportin-5, a protein required for canonical miRNA biogenesis. The biogenesis of these quiescence-induced miRNAs is independent of Exportin-5 and depends instead on Exportin-1. Moreover, these quiescence-induced primary miRNAs (pri-miRNAs) are modified with a 2,2,7-trimethylguanosine (TMG)-cap, which is known to bind Exportin-1, and knockdown of Exportin-1 or trimethylguanosine synthase 1, responsible for (TMG)-capping, inhibits their biogenesis. Surprisingly, in quiescent cells Exportin-1-dependent pri-miR-34a is present in the cytoplasm together with a small isoform of Drosha, implying the existence of a different miRNA processing pathway in these cells. Our findings suggest that during quiescence the canonical miRNA biogenesis pathway is down-regulated and specific miRNAs are generated by an alternative pathway to regulate genes involved in cellular growth arrest.M ost metazoan cells enter a reversible cell-cycle arrest known as "cellular quiescence" when they are exposed to antimitogenic signals or an environment unfavorable for proliferation (1, 2). In mammalian cells, quiescence (also known as "G 0 arrest") is characterized by reduced DNA replication, altered metabolism, increased autophagy, and increased expression of cyclin-dependent kinase inhibitors such as p27 Kip1 (3,4). In vitro, quiescence can be induced in primary cells by serum starvation, contact inhibition, and loss of adhesion to a substrate (5). Quiescence is involved in important cellular processes, including the balance between differentiation and self-renewal in different types of stem cells, and dysregulation of quiescence could favor carcinogenesis. However, the molecular mechanisms that regulate quiescence are poorly understood (6). miRNAs are small, noncoding RNAs ∼22-nt long that regulate the expression of protein-coding genes by base-pairing with the 3′ UTR of mRNAs, repressing the translation and/or inducing the degradation of the target mRNA (7,8). In canonical miRNA biogenesis in mammalian cells, miRNAs are transcribed by RNA polymerase II to produce 7-methylguanosine (m 7 G)-capped primary miRNAs (pri-miRNAs) containing one or more bulged hairpin structures that are recognized by the nuclear microprocessor, which consists of the RNase III enzyme Drosha and the dsRNA-binding protein DGCR8 (DiGeorge syndrome critical region gene 8) (9-12). Specific cleavage of the pri-miRNA by the nuclear microprocessor generates an ∼70-nt stem-loop structure known as the "precursor miRNA" (pre-miRNA), which is recognized and transported to the cytoplasm by 10,11,13). Subsequently, pre-miRNA is cleaved by the cytoplasmic RNase III enzyme Dicer (14-17), generating a double-stranded mature mi...

show abstract

Section: Exportin-1 Is Required For Processing Of Quiescence-induced mentioning

confidence: 99%

An Exportin-1–dependent microRNA biogenesis pathway during human cell quiescence

Martínez

Hayes

Barr

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…There are also reports that some cellular miRNAs display nuclear localization (31,32). To examine localization of m169 and miR-27, we carried out in situ hybridizations with digoxigenin (DIG)-labeled probes directed against these RNAs in uninfected and infected cells.…”

Section: High-throughput Identification Of MCMV Rnas Associated Withmentioning

confidence: 99%

Murine cytomegalovirus encodes a miR-27 inhibitor disguised as a target

Libri

Helwak

Miesen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

132

115

View full text Add to dashboard Cite

Individual microRNAs (miRNAs) are rapidly down-regulated during conditions of cellular activation and infection, but factors mediating miRNA turnover are poorly understood. Infection of mouse cells with murine cytomegalovirus (MCMV) induces the rapid down-regulation of an antiviral cellular miRNA, miR-27. Here, we identify a transcript produced by MCMV that binds to miR-27 and mediates its degradation. UV-crosslinking and high-throughput sequencing [CRAC (UV-crosslinking and analysis of cDNA)] identified MCMV RNA segments associated with the miRNA-binding protein Argonaute 2 (Ago2). A cluster of hits mapped to a predicted miR-27-binding site in the 3′UTR of the previously uncharacterized ORF, m169. The expression kinetics of the m169 transcript correlated with degradation of miR-27 during infection, and m169 expression inhibited miR-27 functional activity in a reporter assay. siRNA knockdown of m169 demonstrated its requirement for miR-27 degradation following infection and did not affect other host miRNAs. Substitution of the miR-27-binding site in m169 to create complementarity to a different cellular miRNA, miR-24, resulted in down-regulation of only miR-24 following infection. The m169 transcript is cytoplasmic, capped, polyadenylated, and interacts with miRNA-27 through seed pairing: characteristic features of the normal messenger RNA (mRNA) targets of miRNAs. This virus-host interaction reveals a mode of miRNA regulation in which a mRNA directs the degradation of a miRNA. We speculate that RNA-mediated miRNA degradation could be a more general viral strategy for manipulating host cells.V iruses devote a large portion of their genomes to strategies for manipulating host cells and evading antiviral defense mechanisms. Numerous host miRNA-binding sites have been predicted in different viral genomes, but the validity and functional relevance of most predictions remain unclear. The best studied miRNA-virus interactions demonstrate that RNA viruses can use cellular miRNAs to regulate their life cycles; for example, the interaction between hepatitis C virus and miR-122 enhances viral replication (1), whereas the interaction between HIV-1 and miR-29 mediates its localization to P bodies (2). Direct interactions between host miRNAs and viral genes can also suppress viral gene expression and replication (3-6) (reviewed in Ref. 7). However, the factors driving the evolution of these interactions remain somewhat controversial, because they may relate to viral mechanisms for persistence and latency rather than host defense (8, 9). At the same time, the expression levels of specific miRNAs can indirectly influence infections; miRNAs are key components of the innate immune response (10, 11) and exert antiviral properties by modulating host cofactors and pathways required by viruses (12-15). We previously showed that miR-27 limits the replication capacity of murine cytomegalovirus (MCMV) but is rapidly degraded during the lytic infection (16). Actinomycin D treatment upon infection prevents miR-27 down-regulation, suggest...

show abstract

“…Castanotto et al provided the fi rst evidence that Exportin-1 allowed the nuclear-cytoplasmic shuttling of mature miRNAs (Castanotto et al, 2009). Furthermore, they showed that while Exportin-1 coimmunoprecipitated with nuclear proteins such as Topo2α and EZH2, it also interacted with Argonaute recent literature on these unconventional miRNAs and hypothesize about their biological signifi cance.…”

Section: Nuclear-cytoplasmic Transport Of Mirnas and Argonaute Proteinsmentioning

confidence: 99%

“…& family members such as Argonaute 1 (AGO1) and Argonaute 2 (AGO2) (Castanotto et al, 2009). Interestingly, Zisoulis et al also showed that the depletion of Exportin-1 by RNA interference resulted in a reduction of the nuclear localization of Argonaute-like Gene 1 (ALG-1), the Argonaute protein in C. elegans, but did not affect total ALG-1 levels (Zisoulis et al, 2012).…”

Section: Mini-review Protein Cellmentioning

confidence: 99%

Nuclear microRNAs and their unconventional role in regulating non-coding RNAs

Liang¹,

Zhang²,

Zen³

et al. 2013

Protein Cell

View full text Add to dashboard Cite

MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that are involved in post-transcriptional gene regulation. It has long been assumed that miRNAs exert their roles only in the cytoplasm, where they recognize their target protein-coding messenger RNAs (mRNAs), and result in translational repression or target mRNA degradation. Recent studies, however, have revealed that mature miRNAs can also be transported from the cytoplasm to the nucleus and that these nuclear miRNAs can function in an unconventional manner to regulate the biogenesis and functions of ncRNAs (including miRNAs and long ncRNAs), adding a new layer of complexity to our understanding of gene regulation. In this review, we summarize recent literature on the working model of these unconventional miRNAs and speculate on their biological significance. We have every reason to believe that these novel models of miRNA function will become a major research topic in gene regulation in eukaryotes.

show abstract

CRM1 mediates nuclear-cytoplasmic shuttling of mature microRNAs

Cited by 103 publications

References 35 publications

An Exportin-1–dependent microRNA biogenesis pathway during human cell quiescence

An Exportin-1–dependent microRNA biogenesis pathway during human cell quiescence

Murine cytomegalovirus encodes a miR-27 inhibitor disguised as a target

Nuclear microRNAs and their unconventional role in regulating non-coding RNAs

Contact Info

Product

Resources

About