bicoid RNA localization requires specific binding of an endosomal sorting complex

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Abstract
Although bicoid mRNA, the anterior determinant of Drosophila, was the first localized determinant to be identified, it is unclear how it targets the anterior of the Drosophila egg. Uwe Irion and Daniel St Johnston have now identified the specificity factor that couples the RNA to the localization pathway as the ESCRT-II complex. ESCRT-II is involved in sorting proteins endocytosed from the cell surface into the degradation pathway, and also acts as a tumour suppressor. Localization of bicoid mRNA is independent of endosomal sorting, and as rat ESCRT-II also binds RNA, this novel function in mRNA localization appears to be conserved in mammals. Although bicoid mRNA, the anterior determinant of Drosophila, was identified almost 20 years ago, the mechanism of its localization is still largely unclear. Here it is shown that the ESCRT-II complex, known for its role in endosomal protein sorting, also binds specifically to bicoid RNA and is necessary for its localization. bicoid messenger RNA localizes to the anterior of the Drosophila egg, where it is translated to form a morphogen gradient of Bicoid protein that patterns the head and thorax of the embryo. Although bicoid was the first localized cytoplasmic determinant to be identified1,2,3,4, little is known about how the mRNA is coupled to the microtubule-dependent transport pathway that targets it to the anterior, and it has been proposed that the mRNA is recognized by a complex of many redundant proteins, each of which binds to the localization element in the 3′ untranslated region (UTR) with little or no specificity5. Indeed, the only known RNA-binding protein that co-localizes with bicoid mRNA is Staufen, which binds non-specifically to double-stranded RNA in vitro6,7. Here we show that mutants in all subunits of the ESCRT-II complex (VPS22, VPS25 and VPS36) abolish the final Staufen-dependent step in bicoid mRNA localization. ESCRT-II is a highly conserved component of the pathway that sorts ubiquitinated endosomal proteins into internal vesicles8,9, and functions as a tumour-suppressor by removing activated receptors from the cytoplasm10,11. However, the role of ESCRT-II in bicoid localization seems to be independent of endosomal sorting, because mutations in ESCRT-I and III components do not affect the targeting of bicoid mRNA. Instead, VPS36 functions by binding directly and specifically to stem-loop V of the bicoid 3′ UTR through its amino-terminal GLUE domain12, making it the first example of a sequence-specific RNA-binding protein that recognizes the bicoid localization signal. Furthermore, VPS36 localizes to the anterior of the oocyte in a bicoid-mRNA-dependent manner, and is required for the subsequent recruitment of Staufen to the bicoid complex. This function of ESCRT-II as an RNA-binding complex is conserved in vertebrates and may clarify some of its roles that are independent of endosomal sorting.