Abstract
SummaryThe cell nucleus is surrounded by a double membrane. The lipid packing and viscosity of membranes is critical for their function and is tightly controlled by lipid saturation. Circuits regulating the lipid saturation of the outer nuclear membrane (ONM) and contiguous endoplasmic reticulum (ER) are known. However, how lipid saturation is controlled in the inner nuclear membrane (INM) has remained enigmatic. Using INM biosensors and targeted genetic manipulations, we show that increased lipid unsaturation causes a reprogramming of lipid storage metabolism across the nuclear envelope (NE). Cells induce lipid droplet (LD) formation specifically from the distant ONM/ER, whereas LD formation at the INM is suppressed. In doing so, unsaturated fatty acids are shifted away from the INM. We identify the transcription circuits that topologically reprogram LD synthesis and identify seipin and phosphatidic acid as critical effectors. Our study suggests a detoxification mechanism protecting the INM from excess lipid unsaturation.
Highlights
The membranes of different organelles vary considerably in lipid composition and functionality (Bigay and Antonny, 2012; van Meer et al, 2008)
Biosensors report nutrient-dependent lipid saturation dynamics of inner nuclear membrane (INM) Since the INM is capable of lipid metabolism, we asked how this specialized membrane territory, adjacent to the genome, responds to changes in lipid saturation
Fluorescently labeled lipid saturation (LipSat) sensors, which measure fatty acyl chain saturation in phospholipids at the INM, or, across the entire endoplasmic reticulum (ER)/nuclear envelope (NE) network
Summary
The membranes of different organelles vary considerably in lipid composition and functionality (Bigay and Antonny, 2012; van Meer et al, 2008). The endoplasmic reticulum (ER) is a complex organelle of highly specialized subdomains comprising the nuclear envelope (NE) and the peripheral ER. The outer nuclear membrane (ONM) and peripheral ER produce glycerophospholipids (or phospholipids in short; PL) for membrane growth, and triacylglycerol (TAG) to stockpile energy (Carman and Han, 2011). Active lipid metabolism at the INM enables cells to store fatty acids (FAs) in nuclear lipid droplets (nLDs) (Barbosa et al, 2019; Romanauska and Kohler, 2018). As a result of its lipid metabolism, the INM has a distinct lipid composition compared with the ONM featuring high levels of diacylglycerol, a precursor for both PL and TAG synthesis. How cells sense and adjust the lipid properties of the INM in various metabolic states is a key open question
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