B02: Coordination of endoplasmic reticulum-associated fidelity machines

The endoplasmic reticulum (ER) is an organelle that coordinates mRNA translation and processing of cytosolic and secretory proteins. Defective fidelity of mRNA and protein biosynthesis triggers the accumulation of misfolded ER proteins, which are typically retrotranslocated to the cytosol for ER-associated protein degradation (ERAD) (Hwang & Qi, 2018). We study the physiological regulation of ER homeostasis in the multicellular organism Caenorhabditis elegans. Our recent work reveals a previously uncharacterized coordination of different ER fidelity machines. In addition to conserved key players of the ERAD pathway, our screen for ER protein accumulation identified mutants of the exo-RNA interference (RNAi) pathway. These findings suggest a novel link between RNA metabolism and protein quality control, which is important for ER homeostasis and organismal integrity. In worms and mouse cells, the conserved Argonaute proteins RDE-1/Ago2 mediate the turnover of ER-associated RNAs induced by ER stress upon tunicamycin treatment or viral infection.

The underlying ER-associated RNA silencing (ERAS) machinery that we have identified triggers mass turnover of mRNAs encoding secretory proteins. Notably, the combination of ERAS- and ERAD-defective mutants results in altered ER morphology and intestinal barrier dysfunction, suggesting complementary roles in ER protein fidelity. The central goal of the proposed research is to understand the spatio-temporal regulation and physiological consequences of mRNA and protein turnover induced by ER stress conditions. The proposed project will address the ERAS-ERAD coordination and systematically analyze: the role of ERAS in the ER stress response (Aim 1), regulation of ERAS-dependent mRNA turnover (Aim 2), the functional crosstalk between ERAS and ERAD (Aim 3), and tissue-specific/neuronal control of the ERAS-ERAD machines (Aim 4), which will provide mechanistic insights into the intricate coordination between mRNA and protein turnover.