Cellular transporter involved in gene silencing - Importin guides switch molecules to their targets
Specific gene-silencing is involved in the development of cancer and plays an essential role in gene regulation. Small noncoding ribonucleic acids (miRNAs) are important regulators of genes. In order to switch off a gene, they interact with so called Argonaute proteins – the subsequent complex induces the shutdown or even degradation of the genetic information. Until now, how this molecular switch works was widely unknown. Scientists of the Max Planck Institute of Biochemistry have now identified the protein Importin 8 as a central factor, that facilitates the switch molecule to find its target (Cell, 6th February, 2009).
Ribonucleic acids (RNAs) carry as messenger-RNAs (mRNAs) genetic information from DNA to cellular protein factories, where they are translated into proteins. But they also have important regulatory functions: Small noncoding RNAs (miRNAs) influence mRNA stability and are able to switch off genes by stalling their translation into proteins. Defects of these regulation processes may lead to cancer and neurodegenerative diseases. Therefore miRNAs are important objects of research and – in the future – could become the basis for new therapeutic strategies.
However, miRNAs can't shut off genes on their own: They need to form complexes with other proteins. As far as humans are concerned, the argonaute protein Ago-2 is the key cellular binding partner of miRNAs: The Ago-miRNA complex binds to mRNA and impedes their translation into proteins – either by blocking the translation process or by initiating RNA decomposition. “While there are a lot of studies concerning miRNA processing, the target mRNA recognition and binding by the Ago-miRNA-complex is only poorly understood”, says Gunter Meister, the head of the research group “RNA biology” at the Max Planck Institute. Now his group has identified the first protein factor which is required for gene-silencing by Ago-miRNA-complexes: Importin 8.
Importin 8 interacts with Ago and miRNA and is necessary for the binding of the AgomiRNA-complex to a variety of mRNA targets: In the cytoplasm – i.e. the intracellular space outside the nucleus – it recruits the complex to its target, allowing for efficient and specific gene-silencing. “Without Importin 8 no mRNA deactivation is possible”, points Lasse Weinmann out, who conducted the study as part of his PhD thesis. Furthermore, the scientists discovered a second mode of action of Importin 8: Importins are molecules that are responsible for the transport of proteins into the nucleus. “As we realised that our new factor is an Importin, it was an obvious supposition that transport processes might play a role in gene-silencing”, explains Meister. Indeed the scientists proved that Importin 8 is involved in the transport of Ago-miRNA-complexes into the nucleus. This is especially interesting, because over the past years there have been controversial discussions as to whether or not small noncoding RNAs occur in the nucleus. “Our findings indicate that the Ago-miRNAcomplex in the nucleus must serve a purpose. Possibly it is involved in gene regulation, too. But it is also conceivable, that there are other, yet unknown, functions”, says Meister, “our results are a beginning to solving these questions”.
Weinmann et al.: Importin Is a Gene Silencing Factor that Targets Argonaute Proteins to Distinct mRNAs; Cell. 2009 Feb 6;136(3):496-507.
Dr. Gunter Meister
Dr. Monika Gödde/Eva-Maria Diehl
Max Planck Institute of Biochemistry
Am Klopferpsitz 18
82152 Martinsried, Germany
Phone: +49 (89) 8578 2824