Translation-associated quality control of protein secretion.

Secreted and membrane proteins (secretome) comprise one-third of our proteome, and are translated at the endoplasmic reticulum (ER). We and others recently discovered a quality control pathway that acts at the earliest stages of secretome biogenesis. Mechanisms underpinning this ER-localized Ribosome- associated Quality Control (ER-RQC) pathway that eliminates stalled ribosomes and aberrant nascent proteins remain largely undefined. Loss of ER-RQC is associated with neurodegenerative and developmental disorders, but the basis for these specific disease outcomes is unknown. This proposal aims to elucidate how ER-RQC maintains secretome integrity by (i) mapping the factors that initiate and resolve ER-RQC, and the proteins that are subject to this pathway; (ii) elucidating the mechanisms that resolve stalled ribosomes and the cellular consequences of defects in this process; (iii) identifying broader translational regulatory pathways that influence secretome biogenesis. We will use state-of-the-art cell engineering to build secretory cell models that link secretome quality control with specific cellular physiology. Our team’s complementary multidisciplinary expertise in structural biology, biochemistry, cell biology, proteomics and genetics positions us perfectly to dissect the pathways that maintain secretome integrity. Our work will advance our understanding of protein quality control, linking the molecular mechanisms underlying these processes to specific failures that cause disease.