Precision tuning of STING signaling: a mutational blueprint

Abstract

In a recent publication in Nature , Zhang et al. present a comprehensive functional atlas of stimulator of interferon genes (STING), a central adaptor of innate immunity. 1 By systematically interrogating thousands of single amino-acid substitutions, the study reveals how distinct structural regions of STING collectively regulate interferon induction, NF-κ B activation and non-canonical autophagy. The work provides a new molecular framework for understanding STING activation, disease-associated variants and future therapeutic modulation of this pathway. STING occupies a central position in innate immune sensing. It functions as the central adaptor downstream of cyclic GMP – AMP synthase (cGAS), which detects cytosolic DNA and generates the second messenger 2 ′ 3 ′ -cGAMP. Binding of 2 ′ 3 ′ -cGAMP induces large conformational rearrangements, oligomerization and traf-fi cking from the endoplasmic reticulum to Golgi and post-Golgi compartments. These events trigger recruitment and activation of TBK1, leading to phosphorylation of IRF3, resulting in type I interferon production, and also promote NF-κ B-dependent in fl ammatory responses. In parallel, STING can induce a non-canonical form of autophagy, linked to LC3B lipidation and, as recently shown, proton-channel activity in post-Golgi membranes. 2 – 4 Through these outputs, STING contributes to host defense against infection, immune surveillance of cancer, cellular senescence and in fl ammatory disease. Its central position has made STING an attractive therapeutic target, with efforts directed both toward agonists, for cancer immunotherapy and vaccine adjuvanticity, and antagonists, for interferonopathies and other in fl ammatory conditions. Yet STING signaling is not a simple on – off switch. It involves ligand binding, conformational transition