SIRT1-mediated deacetylation of TRIM21 promotes IRF5 degradation and restrains type I interferon signatures in Sjögren's disease.

INTRODUCTION

Persistently activated type I interferon (IFN) signaling is a key factor in glandular dysfunction of Sjögren's disease(SjD), with elevated "type I interferon signatures" observed in both peripheral blood and salivary gland tissues of affected patients. However, the intrinsic mechanisms suppressing this response remain incompletely understood. This study aims to investigate whether the NAD⁺-dependent deacetylase SIRT1 regulates the type I IFN signatures in salivary gland tissue by enhancing the ubiquitin-mediated degradation of IRF5 through modulation of TRIM21's E3 ubiquitin ligase activity.

METHODS

Expression of SIRT1, TRIM21, IRF5, and interferon-stimulated genes (ISGs) was analyzed in labial gland tissues from SjD patients and validated in an antigen-induced SjD mouse model and human salivary gland epithelial cells (HSGECs). Protein-protein interactions and post-translational modifications were examined using co-immunoprecipitation, molecular docking, and site-directed mutagenesis approaches.

RESULTS

In SjD patient tissues, mouse models, and IFN-α-stimulated HSGECs, SIRT1 expression was downregulated, whereas TRIM21, IRF5, and interferon-stimulated genes (ISG15, MX1, IFI44, and IFIT3) were significantly upregulated. Activation of SIRT1 attenuated type I IFN signatures by promoting TRIM21-mediated degradation of IRF5 and restoring secretory function in submandibular glands. Mechanistically, SIRT1 enhanced the E3 ubiquitin ligase activity of TRIM21 through site-specific deacetylation at lysine 374, thereby facilitating IRF5 ubiquitination and degradation.

CONCLUSIONS

Our study reveals a novel SIRT1-TRIM21-IRF5 regulatory axis that modulates type I IFN responses in SjD, offering a potential therapeutic target for controlling immune-mediated inflammation in autoimmune diseases.