Roquin binding to target mRNAs involves a winged helix-turn-helix motif

Schuetz, A.; Murakawa, Yuji; Rosenbaum, Eva; Landthaler, Markus; Heinemann, Udo

doi:10.1038/ncomms6701

Cited by 36 publications

(44 citation statements)

References 39 publications

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“…One possibility is that Reg1 can recognize a broader range of SL structures than Roquin. However, crystal structures studies revealed that Roquin ROQ domain interacts with the TNF-CDE stem and a triloop with Py-Pu-Py sequences and that Roquin uses mainly non-sequence-specific contacts with the RNA (Schlundt et al, 2014;Schuetz et al, 2014;Tan et al, 2014). Indeed, we found that overexpression of Roquin could affect 3 0 UTRs harboring a stem without the UUC sequence.…”

Section: Discussionmentioning

confidence: 74%

Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms

Mino

Murakawa

Fukao

et al. 2015

Cell

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Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation.

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Section: Discussionmentioning

confidence: 74%

Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms

Mino

Murakawa

Fukao

et al. 2015

Cell

Self Cite

318

475

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“…Binding of the stem‐loops occurs at the so‐called A‐site, while dsRNA binds at a ‘B‐site’ located between domains I and II, and thus spatially remote from the A‐site (Figures and ). Even though the dsRNA recognition observed by Tan et al is likely to be an artifact of the high RNA concentrations used during crystallization, their findings nevertheless indicate that Roquin‐1 can bind to dsRNA at a second RNA‐binding site. Mutations introduced at each site were used to dissect their individual contributions, and the data suggested that, while the A‐site is critical for mRNA decay, residues in the B‐site may also have an impact on the process …”

Section: Roquin–rna Interactionsmentioning

confidence: 99%

RNA recognition by Roquin in posttranscriptional gene regulation

et al. 2016

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Posttranscriptional regulation of gene expression plays a central role in the initiation of innate and adaptive immune responses. This is exemplified by the protein Roquin, which has attracted great interest during the past decade owing to its ability to prevent autoimmunity. Roquin controls T-cell activation and T helper cell differentiation by limiting the induced expression of costimulatory receptors on the surface of T cells. It does so by recognizing cis regulatory RNA-hairpin elements in the 3' UTR of target transcripts via its ROQ domain-a novel RNA-binding fold-and triggering their degradation through recruitment of factors that mediate deadenylation and decapping. Recent structural studies have revealed molecular details of the recognition of RNA hairpin structures by the ROQ domain. Surprisingly, it was found that Roquin mainly relies on shape-specific recognition of the RNA. This observation implies that a much broader range of RNA motifs could interact with the protein, but it also complicates systematic searches for novel mRNA targets of Roquin. Thus, large-scale approaches, such as crosslinking and immunoprecipitation or systematic evolution of ligands by exponential enrichment experiments coupled with next-generation sequencing, will be required to identify the complete spectrum of its target RNAs. Together with structural analyses of their binding modes, this will enable us to unravel the intricate complexity of 3' UTR regulation by Roquin and other trans-acting factors. Here, we review our current understanding of Roquin-RNA interactions and their role for Roquin function. WIREs RNA 2016, 7:455-469. doi: 10.1002/wrna.1333 For further resources related to this article, please visit the WIREs website.

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“…The NTA is followed by a helix-turn-helix motif. Interestingly, a helix-turnhelix motif contributes to RNA binding of ROQUIN (67)(68)(69), which implicates a candidate for the RNA-interaction in HCLS1. A coiled-coil region represents the main F-actin binding site and functions synergistically with the helix-turn-helix motif (70 -72).…”

Section: Novel Rna-binding Proteins In Macrophagesmentioning

confidence: 99%