UBC Theses and Dissertations
The endoplasmic reticulum diffusion barrier and inter-organelle contact sites Chao, Jesse Tzu-Cheng
Polarization of cellular membranes into domains is an important mechanism to compartmentalize cellular activities within the membrane and establish cell polarity. Recent studies have uncovered that the endoplasmic reticulum (ER) is polarized by diffusion barriers, which in neurons controls glutamate signaling in dendritic spines, but the molecular identity of these diffusion barriers is unknown. In Chapter 2 we show that a direct interaction between integral ER protein Scs2 and septin Shs1 creates the ER diffusion barrier in yeast. We uncovered a new ER-associated polarisome subunit, Epo1, which is required for the tethering of ER to septins. The human homologue of Scs2, VAP-B, also interacts with Shs1 in yeast indicating that the tether may be conserved. As mutations in VAP-B cause amyotrophic lateral sclerosis, loss of ER polarization in dendritic spines is a potential mechanism underlying motorneuron disease. Synthesis of phospholipids, sterols and sphingolipids is thought to occur at contact sites between the ER and other organelles because many lipid synthesizing enzymes are enriched at contact sites. In only a few cases have the enzymes been localized to contacts in vivo and in no instances have the contacts been demonstrated to be required for enzyme function. In Chapter 3 we show that plasma membrane (PM) - endoplasmic reticulum (ER) contact sites in yeast are required for phosphatidylcholine synthesis and regulate the activity of a key enzyme, Opi3, whose activity requires a lipid binding protein, Osh3. Thus, membrane contact sites provide a structural mechanism to regulate lipid synthesis.
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