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Modulation of Ago2 Loading by Cyclophilin 40 Endows a Unique Repertoire of Functional miRNAs during Sperm Maturation in Drosophila

Journal Cell Reports (2020)
Title Modulation of Ago2 Loading by Cyclophilin 40 Endows a Unique Repertoire of Functional miRNAs during Sperm Maturation in Drosophila
Laboratory Germline Biology Group〈Prof. KAI Toshie〉
Abstract

In gene silencing, Hsp90 chaperone machinery assists Argonaute(Ago)-binding and unwinding of silencing small (s)RNA duplexes. This enables formation of effector RNA-induced silencing complex (RISC) often displaying cargo preferences. Hence, in Drosophila, micro(mi)RNAs and small-interfering (si)RNAs are differentially sorted into Ago1-RISC and Ago2-RISC, respectively. Here, we identify fly Cyclophilin 40 (Cyp40) as a testis-specialized Hsp90 co-chaperone essential for spermatogenesis and for modulating Ago2-RISC formation. We show that testis-distinctive Ago-sorting and strand-selection mechanisms accumulate a unique set of miRNAs on Ago2. Cyp40 interacts with duplex-incorporating Ago2 through Hsp90 in vitro, and selectively promotes the build-up of Ago2-bound miRNAs, but not endogenous siRNAs, in vivo. Moreover, one of Cyp40-dependent Ago2-sorted miRNAs is required for late spermatogenesis, unraveling the physiological relevance of the unconventional yet conserved Drosophila miRNA-Ago2 sorting pathway. Collectively, these results identify hitherto unacknowledged RISC-regulatory roles for Hsp90 machinery and, more generally, highlight the tissue-specific adaptation of sRNA pathways through chaperone diversification.

Authors

Taichiro Iki (1), Moe Takami (1), Toshie Kai (1)


  1. Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, 565-0871, Japan.
PubMed 33176138

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