Thomas, Ffion Bryony; (2023) Elucidating roles of ER-PM contacts in polarised secretion and cell growth. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Polarisation, or the formation of structurally and functionally distinct domains, is essential for all cell types. In addition to protein factors that serve as determinants of cellular polarity, lipids are also known to undergo asymmetric distributions within the cell. In particular, phosphatidylinositol 4,5-bisphosphate and phosphatidylserine serve as key landmarks for the recruitment of polarity effector proteins at the plasma membrane (PM). Yet, the regulatory mechanisms that govern their polarised distribution at the PM are poorly understood. My research reveals unexpected roles for the endoplasmic reticulum (ER) in the control of cell polarity. The ER is an expansive membrane compartment that forms close contacts with other organelles as well as the PM. ER-PM contacts are composed of a number of conserved proteins proposed to regulate lipid composition at the PM, including ORP family members (Oxysterol-binding protein-related proteins) and the extended synaptotagmin (E-Syt) proteins. My findings reveal that ORP and E-Syt family members have distinct roles in the control of anionic lipid polarity at the PM. Using yeast cells as a model system, I first describe a role for ORP family members in regulating the anisotropic distribution of phosphoinositide lipids that direct secretory trafficking and polarised growth. I next describe how ORP activity is rapidly attenuated in response to stress conditions that redirect polarised secretion, resulting in alterations in phosphoinositide metabolism and distribution that direct the spatial control of membrane trafficking events. Furthermore, I reveal unprecedented roles of the tricalbins, yeast orthologs of the E-Syts, in directing phosphatidylserine distribution and its polarity effectors including Pkc1 at the plasma membrane in response to stress conditions. Altogether, my findings indicate that switches between ORP and E-Syt activities regulate polarised secretion. In the final chapter of my thesis, I speculate on how the remodelling of ER-PM contacts in yeast may have evolved to direct the spatial and temporal control of polarised trafficking to the apical membrane in epithelial cells and directing cell motility.

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