[R35] Membrane Editing for Deciphering Mechanisms of Phospholipid Homeostasis
Ente: National Institute of General Medical Sciences
Scadenza: 2031-06-30
Importo max: 258.713 EUR
Paese: US
Descrizione
Project Summary/Abstract
Eukaryotic cells and their organelles are bounded by lipid bilayers that act structurally, as permeability barriers,
and as metabolic and signaling hubs. In vitro, a single lipid can produce a fluid bilayer; yet cellular membranes
contain hundreds of lipid species. This complexity in lipid composition has profound functional consequences for
processes occurring at membranes, including ion and metabolite flux, membrane protein folding and
glycosylation, and receptor-mediated signaling. Indeed, disease-associated mutations that impair lipid-modifying
enzyme and transporter function can perturb the lipid makeup of cellular membranes, signifying the physiological
importance of membrane lipid homeostasis. However, the mechanisms by which cells sense and maintain the
proper lipid compositions of each of their organelle membranes are mostly unknown. The most abundant class
of lipids are phospholipids, which play both biophysical and biochemical roles in membrane biology.
Phospholipids are not directly genetically encoded but instead emerge from dynamic metabolism subject to
complex and incompletely understood regulation. Most phospholipids are transported to distant membranes
following their biosynthesis, necessitating the action of lipid transfer proteins to ferry them through the cytosol.
Our understanding of mechanisms regulating phospholipid homeostasis, i.e., metabolism and transport, remains
incomplete. The central goal of my program is to understand how eukaryotic cells regulate biosynthesis and
selective transport of their myriad phospholipids to establish and maintain the correct phospholipid composition
of each organelle membrane. We have begun to elucidate these mechanisms as they pertain to homeostasis of
phosphatidic acid (PA), a prototypical phospholipid that is emblematic of the challenges of studying lipids. PA is
produced by four biosynthetic routes and sits at a highly regulated metabolic branch point upstream of most
other phospholipids and triglycerides. Though its resting levels are low, PA can act as a signaling agent, as
transient bursts of PA engage effectors to elicit effects such as proliferation and migration. To decipher the
pleiotropic metabolic and signaling effects of PA and understand how spatiotemporally distinct PA pools have
unique effects and are regulated differently, we have developed innovative tools for visualizing and manipulating
PA. These tools include bioorthogonal probes for imaging sites of PA biosynthesis and interorganelle lipid
transport, as well as optogenetic membrane editors for spatiotemporal control of PA synthesis on target organelle
membranes. Applying principles learned from these studies, we will expand our toolkit of membrane editors to
target other phospholipid classes. Further, using these tools, we will reveal new mechanisms regulating PA and
phospholipid metabolism. Overall, elucidating fundamental mechanisms of phospholipid homeostasis will shed
light on how dysfunc
Istituzione: CORNELL UNIVERSITY
PI: Jeremy Baskin
Progetto: 1R35GM163777-01
Settori: National Institute of General Medical Sciences
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