NFATc1 drives Orai3 transcription and proteolysis by harnessing epigenome differences in the MARCH8 promoter.

ABSTRACT: Several autonomous mechanisms regulate protein expression, such as transcription, translation, post-translational modifications, and epigenetic changes. Rarely, these processes are controlled by the same molecular player with overlapping roles. Here, we reveal that transcription factor NFATc1 regulates both transcription and degradation of the Ca²⁺ channel Orai3 in a context-dependent manner. We demonstrate that NFATc1 drives Orai3 transcription in non-metastatic pancreatic cancer cells. In invasive and metastatic pancreatic cancer cells, NFATc1 induces Orai3 lysosomal degradation by transcriptionally enhancing MARCH8 E3-ubiquitin ligase. We show that MARCH8 physically interacts with Orai3 intracellular loop eventually resulting in its ubiquitination at the N-terminal. Mechanist

SUBMITTER: Raju S 

PROVIDER: S-EPMC12583688 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature