Antagonizing unfolded protein response of the endoplasmic reticulum by the endoribonuclease ENDU-2/ENDOU

• Applicant: Wenjing Qi, Ph.D.
• Subject Area: Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537144839

In response to accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), cells activate the unfolded protein response (UPR) to trigger a series of complementary adaptive reactions to cope with protein folding stress in the ER. Despite of characterization of multiple signalling pathways activating UPR of ER, it is not well known yet how cells restrict strength of the ER stress response to avoid an overreaction, especially under mild stress condition. Our preliminary results suggest that the endoribonuclease ENDU-2/ENDOU probably acts in a negative feed-back loop to antagonize UPR of ER. Lack of ENDU-2 causes hypersensitivity of animals to mild ER stress without impairing any known UPR sensing pathway. Instead, ENDU-2 inhibition results in an hyperactivation of transcriptional output of UPR of ER and this is regulated at the post-transcriptional level. Here, I suggest to study whether ENDU-2 sits at the ER membrane and specifically promotes mRNA decay of UPR target genes, thereby ensuring a proper stress response according to the protein-folding status in the ER lumen to maintain ER homeostasis.

• DFG Programme: Research Grants