PBLD Orchestrates the STING-Mediated Antiviral Immune Response and Autoimmune Diseases

Precise regulation of stimulator of interferon genes (STING) expression is critical for maintaining immune homeostasis and preventing autoimmune disorders. In this study, phenazine biosynthesis-like domain-containing protein (PBLD) is identified as a key modulator of the STING-dependent antiviral type I interferon (IFN) response by suppressing coiled-coil domain-containing protein 50 (CCDC50)-mediated selective autophagic degradation of STING. Notably, viral infection downregulates PBLD expression through two distinct mechanisms: transcriptional suppression via reduced transcription factor EB (TFEB) activity, and post-translational degradation through an enhanced membrane-associated RING finger protein 2 (MARCH2)-mediated ubiquitin-proteasome pathway. Together, these mechanisms establish a negative feedback loop that facilitates viral immune evasion. Moreover, Pbld -deficient mice exhibit increased susceptibility to human adenovirus type 4 (HAdV-4) infection compared with their wild-type (WT) littermates. Importantly, Pbld- deficiency in the 2,6,10,14-tetramethylpentadecane (TMPD)-induced lupus mice model attenuates STING expression and diminishes autoimmune phenotypes. Clinically, PBLD expression is elevated in patients with systemic lupus erythematosus and positively correlates with STING-driven type I IFN signaling. Taken together, PBLD plays a dual role in STING-mediated innate immunity against viral infection and autoimmunity, highlighting its potential as a therapeutic target for both antiviral infections and autoimmune diseases.