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A putative nuclear function for mammalian Staufen

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In addition to its role in rRNA processing and ribosome assembly, the nucleolus plays a part in the assembly of non-ribosomal ribonucleoprotein particles (RNPs) that are destined for cytoplasmic RNA delivery. Recent evidence indicates that mammalian Staufen2, a brain-specific RNA-binding protein involved in RNA localization, can – at least transiently – enter the nucleolus. Therefore, the assembly of Staufen2 into transport-competent RNPs might occur in the nucleus before their export into the cytoplasm. This could provide new insights into the mechanisms of subcellular RNA localization.

Introduction

The primary function of the nucleolus is the synthesis and processing of rRNAs and their assembly into ribosomal subunits. Several observations suggest that the nucleolus might perform additional functions, including an involvement in export and/or degradation of mRNA, the processing of non-rRNAs transcribed by RNA polymerase III, the modification of small RNAs and the sequestration of regulatory molecules 1, 2, 3. Moreover, a body of evidence suggests that non-ribosomal ribonucleoprotein particles (RNPs) destined for cytoplasmic RNA delivery might assemble in the nucleolus [3]. This is best documented for signal-recognition particles (SRPs) [2] and telomerase-containing particles [4]. Interestingly, a series of independent studies suggests that certain RNA-binding proteins, including nucleolin, La, the fragile-X mental retardation proteins FMRP, FXR1 and FXR2, and Modulo, might be components of non-ribosomal RNPs that transiently enter the nucleolus. These proteins have been previously described as nucleocytoplasmic-shuttling proteins and most of them have been implicated in cytoplasmic RNA localization 3, 5, 6, 7.

Section snippets

The involvement of Staufen in cytoplasmic RNA localization

Staufen belongs to the family of the double-stranded RNA (dsRNA)-binding proteins [8], which contain three-to-five copies of the dsRNA-binding domain (dsRBD) consensus. In Drosophila, the product of the maternal effect gene Stau is required for the transport of oskar mRNA from the anterior to the posterior pole of the oocyte. During its movement, Drosophila Staufen co-localizes with the mRNA in an RNP called the oskar localization complex [9]. Mammals possess two different Staufen genes that

Nucleocytoplasmic shuttling of Stau2

Recently, two independent studies have provided evidence that the brain-specific Stau2 might enter the nucleus in mammalian cells and behave as a nucleocytoplasmic-shuttling protein 13, 14. This is surprising because Drosophila Staufen has only been shown to have roles in RNA localization and translational control in the cytoplasm [9]. When a mutagenesis approach was performed in mice to render Stau2 incompetent for RNA-binding, mutant Stau2 proteins accumulated in the nucleus and, in

Nucleolar sequestration of ADAR proteins

ADAR (adenosine deaminases that act on RNA) proteins also belong to the family of dsRNA-binding proteins and have a role in RNA editing by changing adenosines to inosines in mRNAs. Whereas ADAR2 is mainly found in the nuclear compartment, ADAR1 is predominantly located in the cytoplasm of fibroblasts. Independent studies have shown that ADAR1 and ADAR2 both shuttle in and out of the nucleolus in living cells 17, 18. Further evidence for localization of ADAR proteins to the nucleolus came from

A putative role of the nucleolus in the assembly of non-ribosomal RNPs

In addition to its role in rRNA synthesis, processing, ribosome assembly and maturation, it is now widely accepted that the nucleolus is involved in the biogenesis of SRP and telomerase RNPs, the sequestration of regulatory molecules and possibly even the control of aging. There are several independent observations that a series of non-nucleolar RNA-binding proteins (e.g. La, FMRP, FXR1, FXR 2, Modulo, ADAR1, ADAR2, Stau1 and Stau2) are transiently present in the nucleolus. It is, therefore,

Future perspectives

The biological role for the nucleocytoplasmic shuttling of dsRNA-binding proteins, including Stau2, remains to be elucidated. One important goal will, therefore, be to visualize the transit of wild-type Stau2 into the nucleolus of living cells under normal conditions. Furthermore, it will be interesting to unravel the precise location at which Stau2 recognizes its cargo RNAs and the assembly into transport-competent RNPs occurs. One possible approach could be to interfere with the assembly of

Acknowledgements

A complete reference list will be provided by email upon request. Special thanks go to Eric Arn, Ivan Raska, Heinz Schwarz and Marv Wickens for critical comments on the article. This work has been funded by the Hertie-Foundation, the HFSP, the SFB446 and the Schram-Stiftung (Stifterverband für die deutsche Wissenschaft).

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