NRIP1 disrupts ERα signal in Sjögren's disease via AQP5 suppression and MYC-driven salivary dysfunction

Sjögren's disease (SjD) is marked by dysfunction of the salivary gland (SG) caused by epithelial cell death. However, the mechanism remains unclear. Here we discovered that NRIP1 was abnormally upregulated in SjD and formed a protein complex with estrogen receptor α (ERα) to inhibit saliva secretion and lead to epithelial cell death. NRIP1 interacted with ERα and altered the estradiol (E2)-ERα downstream signal in the SG epithelium. In the context of SjD, NRIP1-ERα suppressed aquaporin-5 (AQP5) expression and promoted MYC expression. The NRIP1-ERα complex bound to the estrogen response elements of the AQP5 promoter, leading to the downregulation of AQP5 expression and reduced SG secretion. Conversely, the NRIP1-ERα complex bound to the estrogen response elements of the MYC promoter, resulting in the upregulation of MYC expression. Furthermore, we demonstrated that elevated MYC levels promoted apoptosis and altered immune regulation and cell metabolism in SjD. Nrip1-knockout/ovariectomized mice did not develop the SjD phenotypes, confirming the role of NRIP1 in the pathophysiology of SjD. Molecular dynamic simulations revealed that NRIP1 competitively bound to ERα and masked the E2 binding site, providing structural insights into the disruption of hormonal signal. This study implicates NRIP1 as a potent diagnosis parameter and provides a putative target for SjD management.