A membrane sensing mechanism couples local lipid metabolism to protein degradation at the inner nuclear membrane

Lipid composition is a determinant of organelle identity; however, whether the inner nuclear membrane (INM) domain of the endoplasmic reticulum (ER) harbors a unique lipid chemistry that contributes to its identity is not known. Here, we demonstrate that a unique INM lipid environment enriched in diacylglycerol protects the nucleo-cytoskeletal linker Sun2 from local degradation by the ubiquitin-proteasome system. A membrane binding amphipathic helix in the nucleoplasmic domain of Sun2 senses INM lipids and is essential to its protein stability. We show that the protein phosphatase CTDNEP1 localizes to the INM to maintain a distinct INM lipid environment necessary for Sun2 accumulation through regulation of the phosphatidic acid phosphatase lipin 1. Thus, the INM lipid environment sculpts the INM proteome via direct lipid-protein interactions that regulate protein stability, which has broad implications for mechanisms of diseases associated with the nuclear envelope.