Journal Article

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

Chen, Xi, Li, Xiaomeng, Watanabe, Nobumoto, Wei, Wei, Wang, Lijing, Mayo, Kevin H., Pathak, Janak L., Qin, Xiuni, Li, Jiang, Li, Xueyang, Mao, Tianjiao, Di, Jun, Chen, Bo, Huo, Yongliang

2026

Overview

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. NRIP1 complex impairs saliva secretion in Sjögren’s disease This study explores Sjögren’s syndrome (SjD), a condition causing dry mouth and eyes, often affecting postmenopausal women. Researchers aimed to understand why salivary gland cells malfunction in SjD. The team found that a protein called NRIP1 is overactive in these cells during SjD. They used mouse models and cell experiments to study this. NRIP1 interacts with another protein, ERα, affecting two key genes: AQP5, which helps with saliva production, and MYC, which influences cell survival and immune response. In SjD, NRIP1 reduces AQP5, leading to less saliva, and increases MYC, causing cell damage. The researchers also discovered that removing NRIP1 in mice prevented SjD symptoms. This suggests that targeting NRIP1 could be a new way to treat SjD. Future research may focus on developing therapies that adjust NRIP1 activity to improve symptoms in patients with SjD. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author. SjD-related phlogosis not only switches off the E2–ERα signal but also activates the NRIP1–ERα signal that downregulates AQP5 expression and upregulates MYC expression to aggravate SjD.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Korean Society for Biochemistry and Molecular Biology,Nature Publishing Group,생화학분자생물학회
• Subject: 17β-Estradiol / 42/41 / 45/61 / 45/91 / 631/337 / 631/80 / 64/60 / 96/95 / Animal models / Animals / Apoptosis / Aquaporin 5 / Aquaporin 5 - genetics / Aquaporin 5 - metabolism / Artificial intelligence / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Biotechnology / Cell culture / Cell death / Cell survival / Datasets / Down-regulation / Epithelial cells / Epithelium / Estrogen Receptor alpha - genetics / Estrogen Receptor alpha - metabolism / Estrogen receptors / Estrogens / Female / Females / Gene Expression Regulation / Genes / Genomes / Humans / Immune response / Immunoregulation / Information technology / Medical Biochemistry / Metabolism / Mice / Mice, Knockout / Molecular Medicine / Myc protein / Nuclear Receptor Interacting Protein 1 - chemistry / Nuclear Receptor Interacting Protein 1 - genetics / Nuclear Receptor Interacting Protein 1 - metabolism / Ovariectomy / Phenotypes / Post-menopause / Promoter Regions, Genetic / Protein Binding / Proteins / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / Reagents / Regulatory sequences / Saliva / Salivary gland / Salivary Glands - metabolism / Salivary Glands - pathology / Salivary Glands - physiopathology / Signal Transduction / Sjogren's syndrome / Sjogren's Syndrome - etiology / Sjogren's Syndrome - genetics / Sjogren's Syndrome - metabolism / Sjogren's Syndrome - pathology / Stem Cells / 생화학