TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus

Abstract

The cGAS-STING signaling pathway serves as a pivotal surveillance mechanism for cytosolic double-stranded DNA (dsDNA) detection in mammalian systems. While STING-mediated type I interferon production is crucial for host defense, sustained activation of this pathway contributes to autoimmune pathologies, including systemic lupus erythematosus (SLE). Maintaining immune homeostasis requires precise regulation of STING activity to prevent hyperactivation. Our study identifies TRIM21 as a novel positive regulator of cGAS-STING signaling in SLE pathogenesis. Our results demonstrate that TRIM21 overexpression stabilizes STING by suppressing autophagic degradation, whereas TRIM21 depletion accelerates this clearance process. Mechanistically, TRIM21 catalyzes the K63-linked polyubiquitylation of the selective autophagy receptor p62/SQSTM1, disrupting its interaction with STING. This post-translational modification prevents the sequestration of STING into autophagosomes, thereby stabilizing the adaptor protein and amplifying downstream type I interferon responses. Our findings reveal a previously unrecognized regulatory circuit in which TRIM21 orchestrates cross-talk between ubiquitin signaling and autophagy to control STING turnover. The TRIM21-p62 axis represents a potential therapeutic target for attenuating pathological interferon production in STING-dependent autoimmune disorders. This work advances our understanding of immune regulation by demonstrating how E3 ligase-mediated ubiquitin modifications modulate cargo recognition in selective autophagy pathways. The identified mechanism provides new insights into the molecular interplay between protein ubiquitylation and autophagic degradation in maintaining the innate immune balance, offering novel perspectives for developing targeted therapies against interferonopathies associated with cGAS-STING hyperactivity.

1. Introduction

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disorder characterized by aberrant immune activation, leading to widespread inflammation and heterogeneous clinical presentations [1]. Contemporary research has highlighted the pivotal role of type I interferon (IFN-I) dysregulation in SLE pathogenesis, where sustained IFN signaling perpetuates immune activation and maintains autoimmune processes [2]. Notably, the cGAS-STING signaling axis has emerged as a critical mediator of type I IFN production and proinflammatory cytokine secretion in innate immune responses [3–5].

The molecular cascade initiates when cytosolic double-stranded DNA (dsDNA) activates cyclic GMP-AMP synthase (cGAS), which catalyzes the synthesis of the second messenger 2′3′-cGAMP [6,7]. This cyclic dinucleotide subsequently binds to and activates stimulator of interferon genes (STING), triggering its translocation from the endoplasmic reticulum to the Golgi apparatus. At this site, STING recruits and phosphorylates TANK-binding kinase 1 (TBK1), which in turn activates interferon regulatory factor 3 (IRF3) through phosphorylation. The nuclear translocation of activated IRF3 ultimately drives the transcription of type I interferons and interferon-stimulated genes (ISGs) [6,8]. Mounting evidence suggests that STING, a central adaptor protein in the cGAS-STING signaling pathway, is involved in the pathogenesis of autoinflammatory and autoimmune disorders [9,10], such as systemic lupus erythematosus, Aicardi-Goutières syndrome (AGS), and STING-associated vasculopathy with onset in infancy (SAVI) [11–13]. This growing body of evidence underscores the critical need for precise regulation of STING activity to maintain immunological equilibrium and prevent autoimmune dysregulation. Importantly, while the involvement of STING in disease pathogenesis is well documented, the comprehensive regulatory network controlling its activation, trafficking, and downstream signaling remains incompletely characterized.

Autophagy serves as an essential cellular quality control mechanism that maintains homeostasis through the encapsulation of damaged organelles, misfolded proteins, and pathogens for lysosomal degradation. In the context of innate immunity, autophagy has been shown to modulate STING signaling by targeting STING for degradation, thereby limiting excessive interferon production. However, the precise molecular mechanisms that regulate STING turnover via autophagy are not fully understood. Our study uncovers a novel regulatory axis involving TRIM21 and p62/SQSTM1 that controls STING stability and type I interferon responses, providing new insights into the pathogenesis of SLE and potential therapeutic strategies.