Spermiogenesis involves gradual chromatin compaction and transcription shut-down. mRNAs that are transcribed in spermatocytes and early-round spermatids are stored as translationally inactive ribonucleoproteins until later during spermiogenesis, when their translation is activated, but how this activation occurs is largely unknown. PIWI proteins and PIWI-interacting RNAs (piRNAs) are essential for gametogenesis as they suppress the expression of transposons and mRNAs. Dai et al. now show that mouse PIWI (MIWI)–piRNAs are the core of a complex required for selective mRNA translation in spermatids.
MIWI–piRNAs target transcripts for silencing through base-pairing between the piRNA and the mRNA 3ʹ untranslated region (3ʹUTR). Working in cells derived from mouse spermatocytes, the authors were surprised to find five piRNAs that strongly upregulated reporters with 3ʹUTRs of the target mRNAs; reporter protein levels but not mRNA levels increased, implicating translation in reporter activation.
Activation of the target-mRNA reporters required piRNA–3ʹUTR base-pairing and 3ʹUTR binding by functional MIWI. Screening for MIWI-interacting proteins revealed that eukaryotic translation initiation factor 3f (eIF3f) directly interacted with MIWI and was also required for reporter activation. The activated 3ʹUTRs included AU-rich elements (AREs) that are bound by HuR, which is an RNA-binding protein known to interact with another translation factor, eIF4G3, for translation in spermatids. Together with the poly(A) binding protein PABPC1, they formed the MIWI–piRNA–eIF3f–HuR–eIF4G3–PABPC1 complex.
MIWI association with eIF3f–HuR was restricted to round spermatids, thus defining the stage of mRNA-specific translation activation. Translation of hundreds of mRNAs co-targeted by piRNA and HuR was dependent on MIWI, indicating that they are direct targets of this selective mechanism of translation activation.
The proteins encoded by two of the five original target mRNAs are essential for sperm acrosome formation. Indeed, severe acrosome defects were found in MIWI-depleted spermatids owing to considerable decrease in the levels of the two proteins.
“MIWI–piRNAs…interact with eIF3f–HuR and other proteins to select a subset of ARE-containing mRNAs for translation activation”
Thus, although MIWI–piRNAs are mostly known for gene silencing, in round spermatids they interact with eIF3f–HuR and other proteins to select a subset of ARE-containing mRNAs for translation activation.
Dai, P. et al. A translation-activating function of MIWI/piRNA during mouse spermiogenesis. Cell 179, 1566–1581 (2019)
About this article
Cite this article
Zlotorynski, E. The other face of PIWI. Nat Rev Mol Cell Biol 21, 66 (2020). https://doi.org/10.1038/s41580-019-0205-4