# PBLD Orchestrates the STING‐Mediated Antiviral Immune Response and Autoimmune Diseases

## TL;DR

PBLD helps control the immune response to viruses and autoimmune diseases by regulating STING, a key protein in the body's defense system.

## Contribution

PBLD is identified as a novel modulator of STING-mediated immunity and autoimmunity through suppression of CCDC50-mediated autophagy.

## Key findings

- PBLD suppresses CCDC50-mediated autophagic degradation of STING to regulate antiviral type I interferon responses.
- PBLD deficiency increases susceptibility to viral infection and reduces autoimmune phenotypes in lupus models.
- PBLD expression is elevated in systemic lupus erythematosus patients and correlates with STING-driven interferon signaling.

## Abstract

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.

During viral infection, PBLD expression is downregulated, thereby subverting host antiviral defenses and promoting viral replication. This study identifies PBLD as a positive regulator of STING‐induced type I interferon activation and delineated the molecular network underlying PBLD‐mediated antiviral immunity and autoimmune pathogenesis, highlighting its potential as a therapeutic target for both antiviral infections and autoimmune diseases.