Fenech, Emma - CAP 37
Defining specificity of homologous machineries resident in the secretory pathway
Introduction
The endoplasmic reticulum (ER) is one of the largest organelles in the cell and serves as the entry point to the secretory pathway, enabling cells to interact with their environment. It performs a wide array of essential cellular functions and each one of these is controlled by pairs, or families, of protein homologs that provide each other with back-up functionality. In addition to this redundancy however, homologs are known to encode differences, and distinguishing these unique properties and functions has been challenging. My research group aims to reveal the mechanisms of specificity through discovering transiently-interacting clients and regulators of homologs resident in the ER and early secretory pathway. In particular, we focus on homologous quality control (QC) machineries, which are critical for organellar, cellular and tissue homeostasis.
Clinical Relevance
Extracellular matrix (ECM) proteins are subject to strict ER QC programs, which are hence critical for the correct formation of the ECM. Many ECM and QC proteins exit the ER and ‘arrive’ at the cis-Golgi where they are partitioned: the latter are recycled back to the ER where they are needed for folding; and the former are further modified and trafficked to the cell periphery, prior to secretion. This ‘partitioning’ is overseen by a family of three retrieval receptor homologs (KDELRs). Why humans need three receptors and which native cargo each homolog is responsible for retrieving, remains poorly characterized. Furthermore, mutations in KDELR2 cause a failure in ECM and QC partitioning and are linked to the connective tissue disorder, Osteogenesis Imperfecta (OI). By investigating KDLER homolog specificity, our research will shed light onto this rare disease mechanism, which will have important therapeutic implications.
Aims
My lab’s aim is to explore the diversification of QC-related homologs and discover the mechanisms which underpin their specific roles in ER homeostasis and beyond – in health and disease. Specifically, we will:
- Establish cutting-edge toolkits to uncover endogenous interaction networks of homologous QC proteins, in a near-native, cellular setting
- Dissect interaction networks to reveal unique clients and regulators of QC homologs
- Characterise secretory pathway defects in disease-linked QC players
Perspective
By uncovering the molecular determinants that drive specificity among ER-resident homologous machineries, we will gain deeper insight into fundamental homeostatic mechanisms and their roles in different disease-states. Ultimately, our findings will illuminate why evolution has generated and maintained so many similar protein machines, and how they make the ER both a robust and an adaptable organelle.
Lab Website
What gives homologous proteins resident in the ER and the early secretory pathway their specificity? The Fenech lab aims to answer this question by developing and employing powerful transient interactomics toolkits.
For more information, please check Fenech Lab.