Biology subjects

Le-Thomas, A.

Publications and source records attributed to Le-Thomas, A..

2 recordsLinked to original sources

bioRxiv2021

Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay

The unfolded protein response (UPR) maintains homeostasis of the endoplasmic reticulum(ER). Residing in the ER membrane, the UPR mediator Ire1 deploys its cytoplasmic kinase-endoribonuclease domain to activate the key UPR transcription factor Xbp1 through non-conventional splicing of Xbp1 mRNA. Ire1 also degrades diverse ER-targeted mRNAs through regulated Ire1-dependent decay (RIDD), but how it spares Xbp1 mRNA from this decay is unknown. We identified binding sites for the RNA-binding protein Pumilio in the 3UTR Drosophila Xbp1. In the developing Drosophila eye, Pumilio bound both the Xbp1unspliced and Xbp1spliced mRNAs, but only Xbp1spliced was stabilized by Pumilio. Furthermore, Pumilio displayed Ire1 kinase-dependent phosphorylation during ER stress, which was required for its stabilization of Xbp1spliced. Human IRE1 could directly phosphorylate Pumilio, and phosphorylated Pumilio protected Xbp1spliced mRNA against RIDD. Thus, Ire1-mediated phosphorylation enables Pumilio to shield Xbp1spliced from RIDD. These results uncover an important and unexpected regulatory link between an RNA-binding protein and the UPR.

cell biology↗

bioRxiv2020

Neuronal regulated Ire1-dependent mRNA decay controls germline differentiation in C. elegans

Understanding the molecular events that regulate cell pluripotency versus acquisition of differentiated somatic cell fate is fundamentally important. Studies in C. elegans demonstrate that knockout of the germline-specific translation repressor gld-1, causes germ cells within tumorous gonads to form germline-derived teratoma. Previously we demonstrated that ER stress enhances this phenotype to suppress germline tumor progression (Levi-Ferber M, 2015). Here, we identify a neuronal circuit that non-autonomously suppresses germline differentiation, and show that it communicates with the gonad via the neurotransmitter serotonin to limit somatic differentiation of the tumorous germline. ER stress controls this circuit through regulated IRE-1-dependent mRNA decay of transcripts encoding the neuropeptide FLP-6. Depletion of FLP-6 disrupts the circuits integrity and hence its ability to prevent somatic-fate acquisition by germline tumor cells. Our findings reveal mechanistically how ER stress enhances ectopic germline differentiation, and demonstrate that RIDD can affect animal physiology by controlling a specific neuronal circuit.

cell biology↗