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Cysteine allostery and autoinhibition govern human STING oligomer functionality
Rebecca Chan1,2,3, Xujun Cao2,3,4, Sabrina L Ergun2,5
1Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.
Nature Chemical Biology
|July 3, 2025
Summary
STING pathway antagonists are needed for inflammatory diseases. This study reveals crucial cysteine modifications in human STING, identifying a peptide for therapeutic development.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- The stimulator of interferon genes (STING) pathway is integral to innate immunity but can drive inflammatory diseases upon aberrant activation.
- A critical need exists for STING antagonists to treat these conditions, yet no inhibitors have reached clinical application due to incomplete understanding of STING activation mechanisms.
- Identifying key steps in human STING activation is essential for developing effective therapeutic inhibitors.
Purpose of the Study:
- To elucidate the precise roles of cysteine palmitoylation in human STING signaling and oligomerization.
- To investigate the functional significance of specific cysteine residues (C64, C91, C148) in STING's post-translational modification and activation.
- To identify novel therapeutic strategies targeting STING activation by exploring its natural autoinhibitory mechanisms.
Main Methods:
- Analysis of cysteine palmitoylation sites in human STING, focusing on C64 and C91.
- Investigation of STING oligomerization and disulfide bond formation at C148.
- Characterization of STING ligand-binding domain self-assembly and scaffolding functions.
- Exploration of STING's autoinhibitory mechanism to identify potential therapeutic targets.
Main Results:
- Palmitoylation at C91 is not essential for human STING signaling.
- Evolutionarily conserved C64 is constitutively palmitoylated and prevents non-productive STING oligomerization.
- Palmitoylation at C64 and C91 influences intradimer disulfide bond formation at C148.
- Dynamic cysteine modifications regulate STING ligand-binding domain assembly and scaffolding.
Conclusions:
- STING activation involves complex, dynamic cysteine post-translational modifications that control self-assembly and function.
- An eight-amino-acid peptide, inspired by STING's autoinhibition, targets the oligomerization interface, presenting a promising avenue for therapeutic development.
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