Abstract
SummaryCell and organelle membranes consist of a complex mixture of phospholipids (PLs) that determine their size, shape, and function. Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic membranes, yet how cells sense and regulate its levels in vivo remains unclear. Here we show that PCYT1A, the rate-limiting enzyme of PC synthesis, is intranuclear and re-locates to the nuclear membrane in response to the need for membrane PL synthesis in yeast, fly, and mammalian cells. By aligning imaging with lipidomic analysis and data-driven modeling, we demonstrate that yeast PCYT1A membrane association correlates with membrane stored curvature elastic stress estimates. Furthermore, this process occurs inside the nucleus, although nuclear localization signal mutants can compensate for the loss of endogenous PCYT1A in yeast and in fly photoreceptors. These data suggest an ancient mechanism by which nucleoplasmic PCYT1A senses surface PL packing defects on the inner nuclear membrane to control PC homeostasis.
Highlights
Eukaryotic cells maintain their membrane lipid composition within narrow limits
In vitro studies have previously suggested that peripheral proteins involved in PL metabolism may directly sense membrane properties in order to maintain membrane homeostasis, but exactly how this occurs in vivo remains uncertain (Cornell, 2016; Cornell and Ridgway, 2015)
We find that Pct1/CCT1/ PCYT1A activity takes place predominantly at the inner nuclear membrane and, in all cell types tested, is promoted by a cellular requirement for membrane biogenesis or remodeling
Summary
Eukaryotic cells maintain their membrane lipid composition within narrow limits. In poikilothermic organisms, changes in membrane composition are essential to preserve membrane fluidity in the cold, whereas in homoeothermic organisms membrane properties are critical for the maintenance of organelle identity and function (Ernst et al, 2016). Recent progress in understanding how cells sense and regulate membrane composition includes characterization of the role of SREBP-2 in regulating endoplasmic reticulum (ER) cholesterol levels (Brown et al, 2017; Eberle et al, 2004) and of the role of Mga in sensing ER membrane acyl chain saturation (Covino et al, 2016; Ernst et al, 2016). In each of these cases, the ‘‘sensors’’ are transmembrane proteins suggested to be detecting primarily the hydrophobic interior milieu of phospholipid (PL) bilayer membranes. In vitro studies have previously suggested that peripheral proteins involved in PL metabolism may directly sense membrane properties in order to maintain membrane homeostasis, but exactly how this occurs in vivo remains uncertain (Cornell, 2016; Cornell and Ridgway, 2015)
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