Project Summary/Abstract
The endoplasmic reticulum (ER) plays a central role in many cellular processes, including lipid metabolism.
The ER network is formed from a single membrane and yet contains functionally distinct subdomains that
allows the ER to regulate lipid metabolism and respond to stress. How this functional diversity is
mechanistically achieved is not well understood. One type of ER subdomain are regions of the ER in close
contact with other organelles, called membrane contact sites (MCSs). They play important roles in cellular
lipid homeostasis, signaling, and stress responses. Other subdomains are regions where some organelles
are formed. One is lipid droplets (LDs), which are lipid storage depots that have many roles in cell
physiology. Here, I take a multidisciplinary approach to address key gaps in our knowledge about
the formation and function of ER subdomains. Central to the projects in this proposal is the question
of how cells control the distribution of lipids within the ER and how this contributes to cellular lipid
homeostasis. There are three directions in the proposal.
1) Direction one addresses key gaps in our understanding of how LD biogenesis occurs and goes
awry in disease. We will leverage a novel in vitro LD biogenesis assay we have developed to
investigate mechanism of LD formation and the roles LD biogenesis proteins. We will also
determine how disease-causing mutations in these proteins alters their functions.
2) Direction two addresses the mechanism and functions of a recently described new family of tube-
like lipid transport proteins that operate MCSs.
3) Direction three addresses a key gap in our knowledge of how the hydrophobic metabolite
Coenzyme Q (CoQ) exits mitochondria and reaches the ER and other compartment and how export
is regulated in response to oxidative stress. Capitalizing on a novel genetic screen we conducted,
we will identify proteins that facilitate and regulate CoQ interorganelle transport.
Collectively, these directions will provide mechanistic insights into the formation and functions of ER
subdomains and how defects in these processes contribute to various diseases.
