The Cellular DExD/H-Box RNA-Helicases UAP56 and URH49 Exhibit a CRM1-Independent Nucleocytoplasmic Shuttling Activity

Thomas, Marco; Lischka, Peter; Müller, Regina; Stamminger, Thomas

doi:10.1371/journal.pone.0022671

Cited by 22 publications

(13 citation statements)

References 72 publications

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“…As in mammalian cells, D. melanogaster and C. elegans [8], [11], [47], both experiments demonstrated that Arabidopsis UAP56 is a predominantly nuclear protein. Recently, it was found that human UAP56 can shuttle between nucleus and cytosol [51], but from our results there is no clear indication for cytosolic localisation of UAP56 in Arabidopsis cells. Rice UAP56 fused to YFP was detected in both nucleus and cytosol of transiently transformed Arabidopsis protoplasts [29], which could be due to overexpression of the fusion protein or due to the use of a heterologous expression system.…”

Section: Discussioncontrasting

confidence: 90%

Arabidopsis DEAD-Box RNA Helicase UAP56 Interacts with Both RNA and DNA as well as with mRNA Export Factors

et al. 2013

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The DEAD-box protein UAP56 (U2AF65-associcated protein) is an RNA helicase that in yeast and metazoa is critically involved in mRNA splicing and export. In Arabidopsis, two adjacent genes code for an identical UAP56 protein, and both genes are expressed. In case one of the genes is inactivated by a T-DNA insertion, wild type transcript level is maintained by the other intact gene. In contrast to other organisms that are severely affected by elevated UAP56 levels, Arabidopsis plants that overexpress UAP56 have wild type appearance. UAP56 localises predominantly to euchromatic regions of Arabidopsis nuclei, and associates with genes transcribed by RNA polymerase II independently from the presence of introns, while it is not detected at non-transcribed loci. Biochemical characterisation revealed that in addition to ssRNA and dsRNA, UAP56 interacts with dsDNA, but not with ssDNA. Moreover, the enzyme displays ATPase activity that is stimulated by RNA and dsDNA and it has ATP-dependent RNA helicase activity unwinding dsRNA, whereas it does not unwind dsDNA. Protein interaction studies showed that UAP56 directly interacts with the mRNA export factors ALY2 and MOS11, suggesting that it is involved in mRNA export from plant cell nuclei.

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Section: Discussioncontrasting

confidence: 90%

Arabidopsis DEAD-Box RNA Helicase UAP56 Interacts with Both RNA and DNA as well as with mRNA Export Factors

et al. 2013

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“…Our data also indicates that there is an additional TAP/p15-dependent step that also occurs within speckles, and likely includes the recruitment of TAP to the mRNA. This step may be coupled with the release of UAP56/URH49, 37 , 38 although it is possible that UAP56/URH49 may stay on the mRNA and accompany it to the cytoplasm 39 . It is thus likely that egress of export-competent mRNAs from the speckles requires TAP/p15 recruitment, and this is consistent with recent findings 26 .…”

Section: Discussionsupporting

confidence: 85%

Trafficking of mRNAs containing ALREX-promoting elements through nuclear speckles

Akef

Zhang

Masuda

et al. 2013

Nucleus

112

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In vertebrates, the majority of mRNAs that encode secreted, membrane-bound or mitochondrial proteins contain RNA elements that activate an alternative mRNA nuclear export (ALREX) pathway. Here we demonstrate that mRNAs containing ALREX-promoting elements are trafficked through nuclear speckles. Although ALREX-promoting elements enhance nuclear speckle localization, additional features within the mRNA largely drive this process. Depletion of two TREX-associated RNA helicases, UAP56 and its paralog URH49, or inhibition of the TREX-associated nuclear transport factor, TAP, not only inhibits ALREX, but also appears to trap these mRNAs in nuclear speckles. mRNAs that contain ALREX-promoting elements associate with UAP56 in vivo. Finally, we demonstrate that mRNAs lacking a poly(A)-tail are not efficiently exported by the ALREX pathway and show enhanced association with nuclear speckles. Our data suggest that within the speckle, ALREX-promoting elements, in conjunction with the poly(A)-tail, likely stimulate UAP56/URH49 and TAP dependent steps that lead to the eventual egress of the export-competent mRNP from these structures.

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“…Importantly, although LGP2 is cytoplasmic and DDX39B nuclear, we found that endogenous DDX39B was also present in the cytoplasm (Fig. 3h), a finding previously noted [32][33][34]. Finally, to validate the role of LGP2 in promoting NF-κB activation in the setting of DDX39B loss, we re-expressed LGP2 in Lgp2 −/− MEFs.…”

Section: Ddx39b Inhibits Nf-κb In Association With Lgp2supporting

confidence: 72%

DDX39B interacts with the pattern recognition receptor pathway to inhibit NF-κB and sensitize to alkylating chemotherapy

Szymura

Bernal

et al. 2020

BMC Biol

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Background: Nuclear factor-κB (NF-κB) plays a prominent role in promoting inflammation and resistance to DNA damaging therapy. We searched for proteins that modulate the NF-κB response as a prerequisite to identifying novel factors that affect sensitivity to DNA damaging chemotherapy. Results: Using streptavidin-agarose pull-down, we identified the DExD/H-box RNA helicase, DDX39B, as a factor that differentially interacts with κB DNA probes. Subsequently, using both RNA interference and CRISPR/Cas9 technology, we demonstrated that DDX39B inhibits NF-κB activity by a general mechanism involving inhibition of p65 phosphorylation. Mechanistically, DDX39B mediates this effect by interacting with the pattern recognition receptor (PRR), LGP2, a pathway that required the cellular response to cytoplasmic double-stranded RNA (dsRNA). From a functional standpoint, loss of DDX39B promoted resistance to alkylating chemotherapy in glioblastoma cells. Further examination of DDX39B demonstrated that its protein abundance was regulated by site-specific sumoylation that promoted its poly-ubiquitination and degradation. These post-translational modifications required the presence of the SUMO E3 ligase, PIASx-β. Finally, genome-wide analysis demonstrated that despite the link to the PRR system, DDX39B did not generally inhibit interferon-stimulated gene expression, but rather acted to attenuate expression of factors associated with the extracellular matrix, cellular migration, and angiogenesis. Conclusions: These results identify DDX39B, a factor with known functions in mRNA splicing and nuclear export, as an RNA-binding protein that blocks a subset of the inflammatory response. While these findings identify a pathway by which DDX39B promotes sensitization to DNA damaging therapy, the data also reveal a mechanism by which this helicase may act to mitigate autoimmune disease.

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The Cellular DExD/H-Box RNA-Helicases UAP56 and URH49 Exhibit a CRM1-Independent Nucleocytoplasmic Shuttling Activity

Cited by 22 publications

References 72 publications

Arabidopsis DEAD-Box RNA Helicase UAP56 Interacts with Both RNA and DNA as well as with mRNA Export Factors

Arabidopsis DEAD-Box RNA Helicase UAP56 Interacts with Both RNA and DNA as well as with mRNA Export Factors

Trafficking of mRNAs containing ALREX-promoting elements through nuclear speckles

DDX39B interacts with the pattern recognition receptor pathway to inhibit NF-κB and sensitize to alkylating chemotherapy

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