In animal gonads, the piRNAs, bound to PIWI-clade Argonaute proteins, silence transposons and maintain genomic integrity. Failure of this pathway triggers transposon activation and induces DNA damage, resulting in sterility. Now, the Hannon, Pillai, and Brennecke labs* describe a new gene in the piRNA pathway, shutdown, which encodes an evolutionarily conserved FKBP-family co-chaperone protein. shutdown was originally discovered in a large-scale Drosophila genetic screen for female sterility (Schupbach and Wieschaus, 1991). Working in flies, the Hannon and Brennecke labs report that mutation of shutdown in fruit fly, like other piRNA pathway genes, leads to transposon de-silencing in both the somatic and germline cells of the ovary. Small RNA sequencing reveals that shutdown mutants block piRNA production. The C-terminal TPR domain of Shutdown can potentially interact with Hsp90, a chaperone protein required to load siRNAs into Argonaute proteins, the Brennecke group mutated an amino acid in Shutdown that is predicted to mediate Hsp90 binding; this mutant does not support piRNA production. Thus, Shutdown may act with Hsp90 to facilitate loading of piRNAs into PIWI proteins.
The Pillai group, working in mice, examined the shutdown homolog FK-506 binding protein 6, fkbp6. As in Drosophila, fkbp6 mutant mice suffered transposon over expression, but in the testes, where piRNAs play their most important role in mammals. Interestingly, in newborn mice, fkbp6 is required for production of Miwi2-, but not Mili-associated piRNAs. Supporting the idea that Shutdown/FKBP6 may collaborate with Hsp90 in piRNA loading, Hsp90 and FKBP6 co-immunoprecipitated from mouse testes extracts; the association required the FKBP6 C-terminal TPR domain.
Thus, the requirement for chaperones to load piRNAs into Piwi proteins appears to be widely conserved in the transposon silencing piRNA pathway.
—Zhao Zhang, University of Massachusetts Medical School
*Preall, J. B., Czech, B., Guzzardo, P. M., Muerdter, F., Hannon, G. J. (2012). shutdown is a component of the Drosophila piRNA biogenesis machinery. RNA 18:1446-57; Olivieri, D., Senti, K. A., Subramanian, S., Sachidanandam, R., Brennecke, J. (2012). The Cochaperone Shutdown Defines a Group of Biogenesis Factors Essential for All piRNA Populations in Drosophila. Mol Cell, in press; Xiol, J. et al. (2012). A Role for Fkbp6 and the Chaperone Machinery in piRNA Amplification and Transposon Silencing. Mol Cell, in press.