Mechanisms at the nexus of membrane protein biogenesis and degradation at the endoplasmic reticulum

Membrane proteins are essential for cellular functions, but the mechanisms ensuring their proteostasis are incompletely understood. Novel protein insertases and intramembrane chaperones have been recently discovered, but their client spectrum and quality control mechanisms have not been understood. We have identified a rhomboid family pseudoprotease UBAC2 as a proximity neighbour of endoplasmic reticulum (ER) insertases, chaperones and ribosomal proteins. UBAC2 is homologous to derlins, the key components of the ER-associated degradation (ERAD) retrotranslocons, and it has been associated with ERAD and lipid metabolism. We will use proteomics and cell biology to characterize the interactome and client spectrum of UBAC2, to understand its role at the nexus of translation and degradation at the ER. The approach will include work in cultured cells, genetics (CRISPR and RNAi), proteomics, and cell biological techniques ranging from microscopy to in vitro biochemical approaches, aiming to elucidate basic principles of membrane protein homeostasis in mammalian cells. The aim of the project is to understand the role of the rhomboid family pseudoprotease UBAC2 in membrane protein biogenesis or degradation at the endoplasmic reticulum and by these means uncover more general principles guiding membrane proteostasis.

Study program: Developmental and cell biology; Molecular and cell biology, genetics and virology; Biochemistry