UPF1 helicase promotes TSN-mediated miRNA decay

Elbarbary, Reyad A.; Miyoshi, Keita; Hedaya, Omar; Myers, Jason R.; Maquat, Lynne E.

doi:10.1101/gad.303537.117

Cited by 35 publications

(27 citation statements)

References 55 publications

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“…While UPF1 is not required in vitro to degrade TumiD targets that either are or are not associated with argonaute 2 (AGO2), which is a core component of miRISCs (Elbarbary et al 2017b), UPF1 promotes TumiD in cells by dissociating miRNAs from their mRNA targets, rendering the miRNAs more susceptible to decay (Elbarbary et al 2017a). TumiD requires UPF1 helicase activity but is not influenced by UPF1 phosphorylation (Elbarbary et al 2017a). How UPF1 helicase activity is derepressed during TumiD is currently unknown.…”

Section: Upf1 In Tsn-mediated Microrna Decay (Tumid)mentioning

confidence: 99%

UPFront and center in RNA decay: UPF1 in nonsense-mediated mRNA decay and beyond

Kim

Maquat

2019

RNA

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168

169

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Nonsense-mediated mRNA decay (NMD), which is arguably the best-characterized translation-dependent regulatory pathway in mammals, selectively degrades mRNAs as a means of post-transcriptional gene control. Control can be for the purpose of ensuring the quality of gene expression. Alternatively, control can facilitate the adaptation of cells to changes in their environment. The key to NMD, no matter what its purpose, is the ATP-dependent RNA helicase upstream frameshift 1 (UPF1), without which NMD fails to occur. However, UPF1 does much more than regulate NMD. As examples, UPF1 is engaged in functionally diverse mRNA decay pathways mediated by a variety of RNA-binding proteins that include staufen, stem-loop-binding protein, glucocorticoid receptor, and regnase 1. Moreover, UPF1 promotes tudor-staphylococcal/ micrococcal-like nuclease-mediated microRNA decay. In this review, we first focus on how the NMD machinery recognizes an NMD target and triggers mRNA degradation. Next, we compare and contrast the mechanisms by which UPF1 functions in the decay of other mRNAs and also in microRNA decay. UPF1, as a protein polymath, engenders cells with the ability to shape their transcriptome in response to diverse biological and physiological needs.

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Section: Upf1 In Tsn-mediated Microrna Decay (Tumid)mentioning

confidence: 99%

UPFront and center in RNA decay: UPF1 in nonsense-mediated mRNA decay and beyond

Kim

Maquat

2019

RNA

Self Cite

168

169

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“…Furthermore, these complexes usually contain adaptor proteins such as RraA (a regulator of RNase E and DEAD-box helicases), RhlB (a DEAD-box RNA helicase) (49), Ski2-like RNA helicases (22, 32) and Suv3 RNA helicase (20). In addition to the RNA degradation, the UPF1 helicase can dissociate miRNAs from their mRNA targets and promote the miRNAs degradation by Tudor-staphylococcal/micrococcal-like nuclease (TSN) (21). The P68 helicase promote unwinding of the human let-7 microRNA precursor duplex, which help let-7 microRNA load into the silencing complex.…”

Section: Discussionmentioning

confidence: 99%

Degradation of miR-466d-3p by JEV NS3 facilitates viral replication and IL-1β expression

Jiang

Zhao

Bai

et al. 2019

Preprint

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27Previous studies revealed that Japanese encephalitis virus (JEV) infection alters the 28 expression of miRNA in central nervous system (CNS). However, the mechanism of JEV 29 infection contributes to the regulation of miRNAs in CNS remain obscure. Here, we found 30 that a global degradation of mature miRNA in mouse brain and neuroblastoma cells after JEV 31 infection. In additional, the integrative analysis of miRNAs and mRNAs suggests that those 32 down-regulated miRNAs are primarily targeted inflammation genes and the miR-466d-3p 33 target the IL-1β which in the middle of those inflammation genes. Transfection of 34 miR-466d-3p decreased the IL-1β expression and inhibited the JEV replication in NA cells. 35 Interestingly, the miR-466d-3p level increased after JEV infection in the presence of 36 cycloheximide, which indicated that viral protein expression reduces miR-466d-3p. 37Therefore, we generated all the JEV coding protein and demonstrated that NS3 is a potent 38 miRNA suppressor. Furthermore, the NS3 of ZIKA virus, WNV, DENV1 and DENV2 also 39 decreased the expression of miR-466d-3p. The in vitro unwinding assay demonstrated that the 40 NS3 could unwind the pre-miR-466d and induce the disfunction of miRNA. Using 41 computational models and RNA immunoprecipitation assay, we found that arginine-rich 42 domains of NS3 are critical for pre-miRNA binding and the degradation of host miRNAs. 43Importantly, site-directed mutagenesis of conserved residues revealed that R226G and 44 R202W significantly reduced the binding affinity and degradation of pre-miR-466d. 45 Together, these results extend the helicase of Flavivirus function beyond unwinding duplex 46 RNA to the decay of pre-miRNAs, which provides a new mechanism of NS3 in regulating 47 miRNA pathways and promoting the neuroinflammation. 48 49 Author Summary 50 Host miRNAs had been reported to regulate JEV induced inflammation in central nervous 51 system. We found that the NS3 of JEV can reduce most of host miRNA expression. The 52 helicase region of the NS3 specifically binds to precursors of miRNA and lead to incorrect 53 unwinding of precursors of miRNAs which inhibits the function of miRNAs. This observation 54 leads to two major findings. First, we identified the miR-466d-3p targets to the host IL-1β and 55 E protein of JEV, and NS3 degrades the miR-466d-3p to promote the brain inflammation and 56 viral replication. Second, we proved that the arginine on the helicase of NS3 is the main 57 miRNA binding sites, and the miRNA degradation by NS3 was abolished when the R226 and 58 R202 were mutated on the NS3. These findings were also confirmed with NS3 of ZIKA virus, 59WNV and DENV which could decrease the expression level of miR-466d-3p to enhance the 60 inflammation. Our study provides new insights into the molecular mechanism of encephalitis 61 caused by JEV, and reveals several amino acid sites to further attenuate the JEV vaccine. 62 63 65 JEV is a single-stranded, positive-sense RNA virus belonging to flavivirus of the Flaviviridae 66 family...

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“…Inosine editing may loosen the base pairing of miRNA precursors and increase their exposure to degradation by TSN. A recent study further shows that TSN interacts with UPF1 helicase which can dissociate miRNA from their mRNA targets, making the mature single-stranded miRNAs susceptible to the TSN-mediated miRNA decay (TumiD) (Elbarbary et al, 2017a (Elbarbary et al, 2017b). As SN1-SN2 and SN3-SN4 are assembled respectively into a structural lobe (see Figure 6), deletion of SN1 or SN4 might disrupt the folding of each lobe and impair TSN's ribonuclease activity, similar to our results of mutations in SN1 and SN3 domains.…”

Section: Discussionmentioning

confidence: 99%

Tudor staphylococcal nuclease is a structure-specific ribonuclease that degrades RNA at unstructured regions during microRNA decay

Yang

Shi

et al. 2018

RNA

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ABSTRACT-binding residues in these two domains strongly impaired its ribonuclease activity. We further show by small-angle X-ray scattering that rice osTSN has a flexible two-lobed structure with open to closed conformations, indicating that TSN may change its conformation upon RNA binding. We conclude that TSN is a structure-specific ribonuclease targeting not only single-stranded RNA, but also unstructured regions of double-stranded RNA. This study provides the molecular basis for how TSN cooperates with RNA editing to eliminate duplex RNA in cell defense, and how TSN selects and degrades RNA during microRNA decay.

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UPF1 helicase promotes TSN-mediated miRNA decay

Cited by 35 publications

References 55 publications

UPFront and center in RNA decay: UPF1 in nonsense-mediated mRNA decay and beyond

UPFront and center in RNA decay: UPF1 in nonsense-mediated mRNA decay and beyond

Degradation of miR-466d-3p by JEV NS3 facilitates viral replication and IL-1β expression

Tudor staphylococcal nuclease is a structure-specific ribonuclease that degrades RNA at unstructured regions during microRNA decay

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