XPO5 promotes primary miRNA processing independently of RanGTP

Wang, Jingjing; Lee, Jerome E.; Riemondy, Kent; Yu, Yanchong; Marquez, Steven M.; Lai, Eric C.; Yi, Rui

doi:10.1038/s41467-020-15598-x

Cited by 25 publications

(18 citation statements)

References 45 publications

(98 reference statements)

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“…This suggests that similar to full length HST, this portion of the protein is necessary for miRNA accumulation but dispensable for miRNA nuclear/cytoplasmic movement. Mammalian EXP5 has recently been shown to be required for miRNA processing in a RAN GTPase-independent manner (Wang et al, 2020). By analogy, our data suggested that a potential export function of HST, if any, and its interaction with RAN1 are dispensable for miRNA movement from the nucleus to the cytoplasm, potentially allowing us to uncouple HST's presumed exportin function from its role in the miRNA pathway.…”

Section: Resultsmentioning

confidence: 51%

“…HST is the plant ortholog of EXPORTIN 5 (EXP5/XPO5), and by analogy with animal systems, HST has been proposed to export miRNAs from the nucleus to the cytoplasm in plants (Brownawell and Macara, 2002). EXP5 also acts independently of its export activity by enhancing pri-miRNA processing efficiency of the DROSHA/DGCR8 microprocessor (Wang et al, 2020). Importantly, the assumption that HST is a miRNA exporter is based on expected functional homology between organisms but is not supported by experimental data, as the subcellular distribution of miRNAs between the nucleus and the cytoplasm is not altered in hst mutants (Park et al, 2005;Zhang et al, 2020;Zhu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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HASTY modulates miRNA biogenesis by linking pri-miRNA transcription and processing

et al. 2021

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Post-transcriptional gene silencing mediated by microRNAs (miRNAs) modulates numerous developmental and stress response pathways. For the last two decades, HASTY (HST), the ortholog of human EX-PORTIN 5, was considered to be a candidate protein that exports plant miRNAs from the nucleus to the cytoplasm. Here, we report that HST functions in the miRNA pathway independent of its cargo-exporting activity in Arabidopsis. We found that Arabidopsis mutants with impaired HST shuttling exhibit normal subcellular distribution of miRNAs. Interestingly, protein-protein interaction and microscopy assays showed that HST directly interacts with the microprocessor core component DCL1 through its N-terminal domain. Moreover, mass spectrometry analysis revealed that HST also interacts independently of its N-terminal domain with the mediator complex subunit MED37. Further experiments revealed that HST could act as a scaffold to facilitate the recruitment of DCL1 to genomic MIRNA loci by stabilizing the DCL1-MED37 complex, which in turn promotes the transcription and proper processing of primary miRNA transcripts (pri-miRNAs). Taken together, these results suggest that HST is likely associated with the formation of the miRNA biogenesis complex at MIRNA genes, promoting the transcription and processing of pri-miRNAs rather than the direct export of processed miRNAs from the nucleus.

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Section: Resultsmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

HASTY modulates miRNA biogenesis by linking pri-miRNA transcription and processing

et al. 2021

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“…Pre-miRNAs are transported through the nuclear pore and then released into the cytoplasm upon the hydrolysis of RanGTP to RanGDP. Intriguingly, exportin 5 has also been reported to promote pri-miRNA processing, which is independent of RanGTP [ 18 ].…”

Section: Biogenesis Of Mirnasmentioning

confidence: 99%

Diagnostic and Therapeutic Implications of microRNAs in Non-Small Cell Lung Cancer

Ahn

2020

IJMS

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microRNAs (miRNAs), endogenous suppressors of target mRNAs, are deeply involved in every step of non-small cell lung cancer (NSCLC) development, from tumor initiation to progression and metastasis. They play roles in cell proliferation, apoptosis, angiogenesis, epithelial-to-mesenchymal transition, migration, invasion, and metastatic colonization, as well as immunosuppression. Due to their versatility, numerous attempts have been made to use miRNAs for clinical applications. miRNAs can be used as cancer subtype classifiers, diagnostic markers, drug-response predictors, prognostic markers, and therapeutic targets in NSCLC. Many challenges remain ahead of their actual clinical application; however, when achieved, the use of miRNAs in the clinic is expected to enable great progress in the diagnosis and treatment of patients with NSCLC.

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“…Accelerates pri-miRNA processing by DROSHA; in complex with SMAD4 activates miRNA precursor transcription upon TGFB/BMP signaling [72,124,125] Export to cytoplasm XPO5 (EXP5) Plays a role in the nuclear export of pre-miRNA to the cytoplasm [138,139]; facilitates the nuclear cleavage of clustered pri-miRNAs [140] RAN Interacts with XPO5; plays a role in the export of pre-miRNA to the cytoplasm [138] Cytoplasmic steps of miRNA biogenesis DICER1 (DICER) RNase III; catalyzes pre-miRNA to miRNA-duplex processing by cutting off the pre-miRNA terminal loop [11,[141][142][143] TARBP2 (TRBP) Coordinates pre-miRNA recognition by DICER1 and the precision of DICER1 cleavage [144,145] PRKRA (PACT)…”

Section: Smad2mentioning

confidence: 99%

A pan-cancer atlas of somatic mutations in miRNA biogenesis genes

Galka-Marciniak

Urbanek-Trzeciak

Nawrocka

et al. 2020

Preprint

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It is a well-known and intensively studied phenomenon that the levels of many miRNAs are differentiated in cancer. miRNA biogenesis and functional expression are complex processes orchestrated by many proteins cumulatively called miRNA biogenesis proteins. To characterize cancer somatic mutations in the miRNA biogenesis genes and investigate their potential impact on the levels of miRNAs, we analyzed whole-exome sequencing datasets of over 10,000 cancer/normal sample pairs deposited within the TCGA repository. We identified and characterized over 3,600 somatic mutations in 29 miRNA biogenesis genes and showed that some of the genes are overmutated in specific cancers and/or have recurrent hotspot mutations (e.g., SMAD4 in PAAD, COAD, and READ; DICER1 in UCEC; PRKRA in OV; and LIN28B in SKCM). We identified a list of miRNAs whose level is affected by particular types of mutations in either SMAD4, SMAD2, or DICER1 and showed that hotspot mutations in the RNase domains in DICER1 not only decrease the level of 5p-miRNAs but also increase the level of 3p-miRNAs, including many well-known cancer-related miRNAs. We also showed an association of the mutations with patient survival. Eventually, we created an atlas/compendium of miRNA biogenesis alterations providing a useful resource for different aspects of biomedical research.

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XPO5 promotes primary miRNA processing independently of RanGTP

Cited by 25 publications

References 45 publications

HASTY modulates miRNA biogenesis by linking pri-miRNA transcription and processing

HASTY modulates miRNA biogenesis by linking pri-miRNA transcription and processing

Diagnostic and Therapeutic Implications of microRNAs in Non-Small Cell Lung Cancer

A pan-cancer atlas of somatic mutations in miRNA biogenesis genes

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