A role for Fkbp6 and the chaperone machinery in piRNA amplification and transposon silencing.
Epigenetic silencing of transposons by Piwi-interacting RNAs (piRNAs) constitutes an RNA-based genome defense mechanism. Piwi endonuclease action amplifies the piRNA pool by generating new piRNAs from target transcripts by a poorly understood mechanism. Here, we identified mouse Fkbp6 as a factor in this biogenesis pathway delivering piRNAs to the Piwi protein Miwi2. Mice lacking Fkbp6 derepress LINE1 (L1) retrotransposon and display reduced DNA methylation due to deficient nuclear accumulation of Miwi2. Like other cochaperones, Fkbp6 associates with the molecular chaperone Hsp90 via its tetratricopeptide repeat (TPR) domain. Inhibition of the ATP-dependent Hsp90 activity in an insect cell culture model results in the accumulation of short antisense RNAs in Piwi complexes. We identify these to be byproducts of piRNA amplification that accumulate only in nuage-localized Piwi proteins. We propose that the chaperone machinery normally ejects these inhibitory RNAs, allowing turnover of Piwi complexes for their continued participation in piRNA amplification.
European Molecular Biology Laboratory, 6 Rue Jules Horowitz, BP 181, 38042 Grenoble, France.
Jordi
J
Xiol
Elisa
E
Cora
Rubina
R
Koglgruber
Shinichiro
S
Chuma
Sailakshmi
S
Subramanian
Mihoko
M
Hosokawa
Michael
M
Reuter
Zhaolin
Z
Yang
Philipp
P
Berninger
Andres
A
Palencia
Vladimir
V
Benes
Josef
J
Penninger
Ravi
R
Sachidanandam
Ramesh S
RS
Pillai
D000818:Animals; D060565:Argonaute Proteins / Q000096:biosynthesis / Q000378:metabolism; D002460:Cell Line; D019175:DNA Methylation; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
D060565:Argonaute Proteins; D018841:HSP90 Heat-Shock Proteins; C546575:PIWIL4 protein, mouse; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D022021:Tacrolimus Binding Proteins; C531061:FKBP6 protein, mouse