Biogenesis of nuclear lipid droplets is regulated by a Sir2-Csa1-Lro1 signaling pathway at the INM

In response to cellular signals, lipid droplets are formed at the inner nuclear membrane (INM), which plays a key role in maintaining membrane homeostasis and energy storage. However, the signaling pathway that regulates nuclear lipid droplet biogenesis remains to be elucidated. Here, we show that in budding yeast, the INM-localized protein Csa1 regulates the localization of the acyltransferase Lro1, which converts diacylglycerol to triacylglycerol, leading to nuclear lipid droplet synthesis. Csa1 possesses two nuclear localization signals, along with an amphipathic helix that anchors it to the INM. Upon nutrient depletion, both Csa1 and Lro1 are enriched at a distinct INM subdomain that abuts the nucleolus, which we term the n-INM. Csa1 interacts with the ubiquitin-conjugating enzyme Ubc4 and protects nuclear Lro1 from degradation by the proteasome. Furthermore, the deacetylase activity of Sir2 is required for the n-INM enrichment of both Csa1 and Lro1. Our findings uncover an unexpected Sir2-Csa1-Lro1 signaling pathway at the INM that regulates nuclear membrane homeostasis.