Dr. Daria Sobańska, M. Eng. Alicja A Komur, Dr. Agnieszka Chabowska-Kita and Prof. Rafał Ciosk (all from the Integrative Biology Team of IBCH PAS) are the authors of the article “The silencing of ets-4 mRNA relies on the functional cooperation between REGE-1/Regnase-1 and RLE-1/Roquin-1” (Nucleic Acids Research, Volume 50, Issue 14, 12 August 2022, Pages 8226–8239, https://doi.org/10.1093/nar/gkac609). The results presented in the article were performed in collaboration with Dr Julita Gumna and Prof. Katarzyna Pachulska-Wieczorek (Department of Structure and Function of Retrotransposons of IBCH PAS) and Dr. Pooja Kumari (University of Oslo).
Regnase-1, also known as Zc3h12a or MCPIP1, is an evolutionarily conserved endoribonuclease that degrades specific mRNAs playing important roles in many biological processes including immune homeostasis, development and cancer. It was initially reported to cooperate with another RNA-binding protein (RBP), Roquin-1, that was suggested to recruit Regnase-1 to specific mRNA targets during T-cell activation. This model is additionally supported by a recent study reporting a physical interaction between these two RBPs important for mRNA silencing. However, other investigations led to an alternative model, postulating that these RBPs regulate mRNAs independently from each other and through entirely different mechanisms.
Results presented in this article, studying the C. elegans ortholog of Regnase-1, called REGE-1 (REGnasE-1), uncovered its functional cooperation with the nematode counterpart of Roquin-1, RLE-1. Although both proteins act non-redundantly, i.e., both are essential for mRNA silencing and their functions appear to be non-additive, REGE-1 and RLE-1 associate with mRNA independently. Interestingly, in contrast to Regnase-1 that is known to target a set of diverse transcripts, analysis presented in the article suggests that REGE-1 targets a single mRNA encoding a conserved transcription factor, ETS-4. Authors propose a model where REGE-1, by controlling the abundance of ETS-4, affects the transcription of diverse downstream genes regulating various aspects of animal physiology. Although REGE-1/Regnase-1 and RLE-1/Roquin-1 are functionally related from nematodes to humans, the exact mechanisms underlying their cooperation appear to vary between species. Thus, data presented in the article provide an unique perspective on the evolution of an important post-transcriptional regulatory mechanism.