The E3 ubiquitin ligase RNF 114 and TAB 1 degradation are required for maternal‐to‐zygotic transition

Abstract

The functional role of the ubiquitin-proteasome pathway during maternal-to-zygotic transition (MZT) remains to be elucidated. Here we show that the E3 ubiquitin ligase, Rnf114, is highly expressed in mouse oocytes and that knockdown of Rnf114 inhibits development beyond the two-cell stage. To study the underlying mechanism, we identify its candidate substrates using a 9,000-protein microarray and validate them using an in vitro ubiquitination system. We show that five substrates could be degraded by RNF114-mediated ubiquitination, including TAB1. Furthermore, the degradation of TAB1 in mouse early embryos is required for MZT, most likely because it activates the NF-jB pathway. Taken together, our study uncovers that RNF114-mediated ubiquitination and degradation of TAB1 activate the NF-jB pathway during MZT, and thus directly link maternal clearance to early embryo development.

RNF114 suppresses tumour metastasis through the regulation of PARP10

“…It has been reported that RNF114 is ampli ed and upregulated in patients with psoriasis but downregulated in the testes of azoospermic patients compared with its level in fertile adult testes [33], suggesting that it may be involved in human diseases, although the underlying molecular mechanism remains largely unde ned. RNF114 substrates that have been reported include P21, which is involved in cell cycle regulation [22], TAB1 involved in maternal-to-zygotic transition [34] and A20 involved in NF-κB activity and T cell activation [35]. In this study, we demonstrated PARP10 as a newly identi ed RNF114 substrate.…”

The maternal-to-zygotic transition revisited

“…The TAB1 kinase inhibits the action of the NFκB transcription factor by retaining it in the cytoplasm. In early embryos, the E3 ubiquitin ligase RnF114 directs degradation of TAB1, permitting translocation of NFκB into the nucleus and, thus, activation the NFκB pathway, which is essential for development (Yang et al, 2017). Indeed, either knockdown of RnF114 or persistence of TAB1 protein prevents development beyond the two-cell stage (Yang et al, 2017).…”

Harnessing the Anti-Cancer Natural Product Nimbolide for Targeted Protein Degradation

“…Previous studies have shown that RNF114 expression is elevated at late G1 phase to regulate p21 and p57 levels and is crucial for G1-to-S phase transition 48 . Other RNF114 substrates that have been reported include TAB1 involved in maternal-to-zygotic transition and A20 involved in NF-kB activity and T cell activation 57,58 . In cancer contexts or other cell and tissue types, nimbolide may thus have additional activities through regulating the levels of other RNF114 protein substrates.…”