piRNA-Triggered MIWI Ubiquitination and Removal by APC/C in Late Spermatogenesis

SummaryThe PIWI/PIWI-interacting RNA (piRNA) machinery has been well documented to maintain genome integrity by silencing transposons in animal germ cells. Recent studies have advanced our understanding of the biogenesis and function of this machinery; however, its metabolism has remained largely unexplored. Here, we show that murine PIWI (MIWI) is degraded through the APC/C-26S proteasome pathway and that piRNAs play an indispensable role in this process by enhancing MIWI interaction with an APC/C substrate-binding subunit. Interestingly, piRNA-triggered MIWI destruction occurs in late spermatids, which in turn leads to piRNA elimination, suggesting a feedforward mechanism for coordinated removal of the MIWI/piRNA machinery at a specific developmental stage. Importantly, the proper removal of MIWI/piRNA is essential for sperm maturation. Together, our results reveal a role for piRNAs in regulating the clearance of the MIWI/piRNA machinery via the ubiquitin-proteosome pathway and demonstrate the critical importance of proper temporal regulation of MIWI/piRNA in male germ cell development.

Graphical AbstractFigure optionsDownload high-quality image (296 K)Download as PowerPoint slideHighlights
► MIWI is a substrate of APC/C, and piRNA loading is essential for MIWI ubiquitination
► piRNA loading promotes MIWI binding to the APC/C substrate-binding subunit
► MIWI and piRNAs are coordinately eliminated in late spermatids
► Inhibition of MIWI destruction in late spermatids prevents sperm maturation