Promiscuity in post‐transcriptional control of gene expression: Drosophila sex‐lethal and its regulatory partnerships

Abstract

The Drosophila RNA‐binding protein Sex‐lethal (Sxl) is a potent post‐transcriptional regulator of gene expression that controls female development. It regulates the expression of key factors involved in sex‐specific differences in morphology, behavior, and dosage compensation. Functional Sxl protein is only expressed in female flies, where it binds to U‐rich RNA motifs present in its target mRNAs to regulate their fate. Sxl is a very versatile regulator that, by shuttling between the nucleus and the cytoplasm, can regulate almost all aspects of post‐transcriptional gene expression including RNA processing, nuclear export, and translation. For these functions, Sxl employs multiple interactions to either antagonize RNA‐processing factors or to recruit various coregulators, thus allowing it to establish a female‐specific gene expression pattern. Here, we summarize the current knowledge about Sxl function and review recent mechanistic and structural studies that further our understanding of how such a seemingly ‘simple’ RNA‐binding protein can exert this plethora of different functions.

Drosophila Sister-of-Sex-lethal is a repressor of translation

“…In Drosophila, sex determination is under the control of the switch gene Sex-lethal (Sxl) which encodes an RNA-binding protein that is expressed only in female flies. Sxl acts on multiple levels, post-transcriptionally controlling the synthesis of key factors involved in sex-specific traits to govern female development (Penalva and Sánchez 2003;Salz and Erickson 2010;Graindorge et al 2011;Salz 2011;Venables et al 2012;Moschall et al 2017).…”

“…To prevent Msl2 protein expression in females, Sxl binds to U-rich elements within the untranslated regions (UTRs) of msl-2 mRNA to control its splicing, export, and translation (Zhou et al 1995;Bashaw and Baker 1997;Kelley et al 1997;Gebauer et al 1998;Merendino et al 1999;Förch et al 2000Förch et al , 2001Graindorge et al 2013). Regulation on several levels and by multiple mechanisms ensures a robust and fail-safe repression of Msl2 protein production to effectively prevent DCC formation in female flies (for review, see Moschall et al 2017).…”

“…Ssx and Sxl exhibit quite distinct N-and C-terminal regions; however, they share a highly similar central domain which in the case of Sxl is sufficient for translational repression of msl-2 mRNA (Grskovic et al 2003;Moschall et al 2017). Intriguingly, Sxl and Ssx have a similar RNA-binding specificity, and in the absence of Sxl, Ssx was found to bind to the U-rich RNA regulatory elements of msl-2 mRNA (Rogell et al 2017); however, the functional consequence of this association remains unknown.…”

Mirroring the multifaceted role of RNA and its partners in gene expression

“…Therefore, the discovery of new types of RNA molecules went hand in hand with the unearthing of new RNA‐binding proteins that specifically or promiscuously interact with RNAs to implement various functions. In this respect, FEBS Letters published recently a series of review articles related to RNA‐binding proteins and their cellular and neuronal functions (https://febs.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1873-3468.MRNATRANSPORT) . The present Special Issue extends this series by highlighting recent topics in RNA research such as RNA modifications, RNA‐RNA and RNA‐protein interactions, and RNA‐regulated pathways.…”

“…. mRNA transport, local translation and processing) [12][13][14][15][16][17]. The present Special Issue extends this series by highlighting recent topics in RNA research such as RNA modifications, RNA-RNA and RNA-protein interactions, and RNAregulated pathways.…”