Roles of the CTDNEP1-NEP1R1 phosphatase complex at the nuclear envelope

The nuclear envelope (NE) is a dynamic structure that is continuously remodelled to meet different cellular demands. Changes in NE dynamics and mutations in NE proteins have been implicated in pathological conditions. CTDNEP1-NEP1R1 is a conserved NE phosphatase complex, with a previously identified role in regulating NE biogenesis by dephosphorylating lipin, a phosphatidic acid hydrolase critical for lipid homeostasis. Recent work in the lab showed that CTDNEP1-NEP1R1 also regulates the degradation of an inner nuclear membrane protein SUN2, a subunit of the LINC complex involved in mechanotransduction across the NE. This finding prompted us to search for novel functions of CTDNEP1-NEP1R1 in the NE through proteomics studies. Co-immunoprecipitation of CTDNEP1 and NEP1R1 identified MAN1 as an inner nuclear membrane interactor of the phosphatase complex, and together play a role in the TGF-β/BMP signalling pathway. Domain mapping, mutagenesis and functional assays provided mechanistic basis of the CTDNEP1-NEP1R1-MAN1 complex for TGF-β/BMP signalling inactivation. In addtion, phosphoproteomics further nominates additional substrates of CTDNEP1-NEP1R1 at the NE and ER, indicating potentially broader functions of CTDNEP1-NEP1R1 beyond lipid biogenesis.