Abstract
P bodies (PBs) and stress granules (SGs) are conserved cytoplasmic aggregates of cellular messenger ribonucleoprotein complexes (mRNPs) that are implicated in mRNA metabolism and play crucial roles in adult stem cell homeostasis and stress responses. However, the mechanisms underlying the dynamics of mRNP granules are poorly understood. Here, we report NEDD4, an E3 ubiquitin ligase, as a key regulator of mRNP dynamics that controls the size of the spermatogonial progenitor cell (SPC) pool. We find that NEDD4 targets an RNA-binding protein, NANOS2, in spermatogonia to destabilize it, leading to cell differentiation. In addition, NEDD4 is required for SG clearance. NEDD4 targets SGs and facilitates their rapid clearance through the endosomal–lysosomal pathway during the recovery period. Therefore, NEDD4 controls the turnover of mRNP components and inhibits pathological SG accumulation. Accordingly, we propose that a NEDD4-mediated mechanism regulates mRNP dynamics, and facilitates SPC homeostasis and viability under normal and stress conditions.
Highlights
P bodies (PBs) and stress granules (SGs) are conserved cytoplasmic aggregates of cellular messenger ribonucleoprotein complexes that are implicated in messenger RNA (mRNA) metabolism and play crucial roles in adult stem cell homeostasis and stress responses
To further test whether NANOS2 could be ubiquitinated by endogenous NEDD4 or not, we introduced MYC-NANOS2 to mouse embryonic fibroblast (MEF) cells established from both wild type (WT) and Nedd[4] knockout (KO) mice
An elaborate post-transcriptional network involving messenger ribonucleoprotein complexes (mRNPs) granules controls the fate of many adult stem cells[1,6]
Summary
P bodies (PBs) and stress granules (SGs) are conserved cytoplasmic aggregates of cellular messenger ribonucleoprotein complexes (mRNPs) that are implicated in mRNA metabolism and play crucial roles in adult stem cell homeostasis and stress responses. Post-transcriptional regulation of messenger RNA (mRNA) translation, sequestration and degradation plays a crucial role in modulating appropriate spatiotemporal gene expression This RNA-based regulation influences many biological processes, including stem cell homeostasis, embryogenesis and stress response[1,2,3]. Due to the critical functions of these mRNPs in SSCs and the possible connection to stress-related diseases, it is important to understand the mechanisms that modulate the assembly of PBs and SGs, and their disassembly and clearance from SSCs. One possible regulator is an E3 ubiquitin ligase, NEDD4 (neural precursor cell expressed developmentally downregulated protein 4-1), which is coimmunoprecipitated with NANOS2 in male gonads. We find that the NEDD4 complex regulates mRNP dynamics by targeting mRNP to the lysosomal degradation pathway under normal and heat-stress conditions, facilitating differentiation and survival of SPCs under stress
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