HSP90α plays an important role in piRNA biogenesis and retrotransposon repression in mouse.

Tomoko Ichiyanagi,Kenji Ichiyanagi,Shinichiro Chuma,Satomi Kuramochi-Miyagawa,Hiroyuki Sasaki,Heiichiro Udono,Ayako Ogawa,Toru Nakano

doi:10.1093/nar/gku881

Abstract

HSP90, found in all kingdoms of life, is a major chaperone protein regulating many client proteins. We demonstrated that HSP90α, one of two paralogs duplicated in vertebrates, plays an important role in the biogenesis of fetal PIWI-interacting RNAs (piRNA), which act against the transposon activities, in mouse male germ cells. The knockout mutation of Hsp90α resulted in a large reduction in the expression of primary and secondary piRNAs and mislocalization of MIWI2, a PIWI homolog. Whereas the mutation in Fkbp6 encoding a co-chaperone reduced piRNAs of 28–32 nucleotides in length, the Hsp90α mutation reduced piRNAs of 24–32 nucleotides, suggesting the presence of both FKBP6-dependent and -independent actions of HSP90α. Although DNA methylation and mRNA levels of L1 retrotransposon were largely unchanged in the Hsp90α mutant testes, the L1-encoded protein was increased, suggesting the presence of post-transcriptional regulation. This study revealed the specialized function of the HSP90α isofom in the piRNA biogenesis and repression of retrotransposons during the development of male germ cells in mammals.

Highlights

Heat-shock protein 90 (HSP90), the most abundant protein in mammalian cells, is a chaperone that stabilizes the conformation of >200 client proteins in various physiological pathways, thereby maintaining cellular homeostasis [1,2]
The Tudor domains in various proteins bind to methylated arginine residues [31], and it has been postulated that the MIWI2-TDRD9 interaction depends on the methylation of arginine residue(s) in MIWI2 at its RA/RG motifs, which is likely catalyzed by an arginine methyltransferase, PRMT5 [32,33]
The level of arginine methylation was comparable between WT and KO preparations, suggesting that the arginine methylation of MIWI2 is not disturbed in Hsp90α KO mice

Summary

Introduction

Heat-shock protein 90 (HSP90), the most abundant protein in mammalian cells, is a chaperone that stabilizes the conformation of >200 client proteins in various physiological pathways, thereby maintaining cellular homeostasis [1,2]. Hsp90β is ubiquitously expressed (constitutive type), Hsp90α expression is increased in response to various stresses (inducible type), and its expression is more tissue-specific at the steady state, being relatively higher in the testes and brain [3,4,5]. Whether these HSP90 proteins have specific functions remains unclear. Silkworm Hsp participates in the loading of piRNA precursors onto Piwi [13] Another Hsp co-chaperone, Shutdown, is important for piRNA production in flies [14], and its mouse ortholog, FKBP6, has been proposed to facilitate the recycling of PIWI proteins in piRNA biogenesis

Methods

Results

Conclusion