Introduction and Objective: The protein kinase A (PKA) signaling cascade is the core signaling pathway of hepatic gluconeogenesis. However, the mechanisms governing PKA nuclear translocation remain incompletely understood. In this study, we identified the nuclear membrane protein TMEM201 (transmembrane protein 201) as a critical regulator of PKA nuclear translocation.Methods: PKA catalytic subunits were used as bait in cross-linking immunoprecipitation assays to identify proteins involved in PKA nuclear translocation. The functional role of TMEM201 was further evaluated using primary mouse hepatocyte gluconeogenesis assays and TMEM201 knockout mouse models.Results: Loss of TMEM201 significantly inhibited PKA nuclear translocation and suppressed gluconeogenesis in primary mouse hepatocytes. Consistently, TMEM201 knockout mice exhibited reduced gluconeogenic capacity, as demonstrated by pyruvate tolerance and glucagon tolerance tests. Mechanistically, TMEM201 was localized to the nuclear pore complex and regulated PKA nuclear translocation through its unique C-terminal domain.Conclusion: TMEM201 functions as a previously unrecognized regulator of PKA catalytic subunit nuclear translocation and plays a critical role in the control of hepatic gluconeogenesis.
H. Guo: None.
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