Lipid composition determines organelle identity; however, whether the lipid composition of the inner nuclear membrane (INM) domain of the ER contributes to its identity is not known. Here, we show that the INM lipid environment of animal cells is under local control by CTDNEP1, the master regulator of the phosphatidic acid phosphatase lipin 1. Loss of CTDNEP1 reduces association of an INM-specific diacylglycerol (DAG) biosensor and results in a decreased percentage of polyunsaturated containing DAG species. Alterations in DAG metabolism impact the levels of the resident INM protein Sun2, which is under local proteasomal regulation. We identify a lipid-binding amphipathic helix (AH) in the nucleoplasmic domain of Sun2 that prefers membrane packing defects. INM dissociation of the Sun2 AH is linked to its proteasomal degradation. We suggest that direct lipid-protein interactions contribute to sculpting the INM proteome and that INM identity is adaptable to lipid metabolism, which has broad implications on disease mechanisms associated with the nuclear envelope.
© 2023 Lee et al.