Prof. Chengjiang Gao group reveals the negative regulation of anti-fungal immunity by STING
Source：Chengjiang Gao
2023-07-25
On Jun. 27th, the Cell Press journal IMMUNITY published the research article “The nucleotide receptor STING translocates to the phagosomes to negatively regulate anti-fungal immunity”. This study demonstrated that STING exhibits a previously unrecognized negative regulation on anti-fungal immunity, which is unlike its canonical positive role in anti-viral immune responses. Tian Chen, as the assistant research fellow from the School of Biomedical Sciences of Shandong University is the first author, and Prof. Chengjiang Gao from the School of Biomedical Sciences of Shandong University is the corresponding author.
Candida species are the most common human fungal pathogens with up to approximate 40% mortality. Candida species colonize the human oral, genital and gastrointestinal tracts and skin as commensals; they can also cause mucosal or systemic infections under certain life-threatening conditions. The current antifungal drugs for systemic infections have limitations including drug toxicity and resistance. A better understanding of the anti-fungal immunity will improve our future therapeutic development.
STING (Stimulator of Interferon Genes) is essential for host immune defense against bacterial and viral infections. It senses endogenous cyclic dinucleotides, such as 2, 3-cyclic GMP-AMP (2, 3-cGAMP) synthesized by cGAS (cyclic GMP-AMP synthase); it also senses exogenous cyclic dimeric guanosine and adenosine monophosphates (c-di-GMP, c-di-AMP) from bacteria. It provides protection against these cellular stresses via triggering the synthesis of interferon (IFN) and other cytokines, as well as autophagy. However, it remains unknown if STING plays a role in anti-fungal immunity.
In this study, Chen et al. studied the role of STING in combating the fungal pathogen C. albicans infection, which possesses totally distinct pathogenicity mechanisms from that of DNA viruses. They identified the negative effect for STING in modulating the activation of C-type lectin receptor (CLR)- associated signaling cascades towards fungal infection. Upon fungal stimulation, STING was translocated to the phagosome, a membrane organelle confining and degrading the pathogen. The transit patterns that STING responds to in the context of fungal challenge was different from the canonical trafficking route where STING was stimulated by cGAMP, where it moves to the Golgi apparatus from the ER. Biochemical analysis demonstrates that STING bound directly with Src via its first 18 amino acids, and this prohibited the formation of Syk and Src complex. Src further triggered STING tyrosine phosphorylation at Y245 locus, and this modification suppressed Syk activation. Furthermore, it was found that STING negatively modulated anti-fungal immunity in systemic fungal infection of the mouse model. Administration of the 18-aa peptide of STING at N-terminus improved the survival rate of mice when injected C. albicans intravenously.
The highlights of this study include: (1) STING-deficient mice exhibit enhanced anti-fungal immunity upon C. albicans infection. (2) STING translocates to the phagosomes upon C. albicans infection. (3) STING binds to Src via the N-terminal 18-aa motif to inhibit Syk-mediated signaling. (4) The N-terminal 18-aa peptide of STING improves host outcome toward fungal infection. This study was selected in Research Highlights by Nature Reviews Immunology (NRI), which was published on Jul. 10th, for its importance of revealing the negative regulation in response to fungal infection by STING.
Prof. Gao group focus on studying the mechanisms by which the immune signal transduction controls microbial infections. As the corresponding author, Prof. Gao has published high-profile journals including Nat Immunol, Nat Commun, J Exp Med, Cell Rep, PLOS Pathog. This work was supported by grants from the National Natural Science Foundation of China, the National key research and development program. This work was also supported by China Postdoctoral Science Foundation, and Future Scholar Program of Shandong University.
Article DOI：https://doi.org/10.1016/j.immuni.2023.06.002
NRI Research highlight：https://doi.org/10.1038/s41577-023-00916-3
Candida species are the most common human fungal pathogens with up to approximate 40% mortality. Candida species colonize the human oral, genital and gastrointestinal tracts and skin as commensals; they can also cause mucosal or systemic infections under certain life-threatening conditions. The current antifungal drugs for systemic infections have limitations including drug toxicity and resistance. A better understanding of the anti-fungal immunity will improve our future therapeutic development.
STING (Stimulator of Interferon Genes) is essential for host immune defense against bacterial and viral infections. It senses endogenous cyclic dinucleotides, such as 2, 3-cyclic GMP-AMP (2, 3-cGAMP) synthesized by cGAS (cyclic GMP-AMP synthase); it also senses exogenous cyclic dimeric guanosine and adenosine monophosphates (c-di-GMP, c-di-AMP) from bacteria. It provides protection against these cellular stresses via triggering the synthesis of interferon (IFN) and other cytokines, as well as autophagy. However, it remains unknown if STING plays a role in anti-fungal immunity.
In this study, Chen et al. studied the role of STING in combating the fungal pathogen C. albicans infection, which possesses totally distinct pathogenicity mechanisms from that of DNA viruses. They identified the negative effect for STING in modulating the activation of C-type lectin receptor (CLR)- associated signaling cascades towards fungal infection. Upon fungal stimulation, STING was translocated to the phagosome, a membrane organelle confining and degrading the pathogen. The transit patterns that STING responds to in the context of fungal challenge was different from the canonical trafficking route where STING was stimulated by cGAMP, where it moves to the Golgi apparatus from the ER. Biochemical analysis demonstrates that STING bound directly with Src via its first 18 amino acids, and this prohibited the formation of Syk and Src complex. Src further triggered STING tyrosine phosphorylation at Y245 locus, and this modification suppressed Syk activation. Furthermore, it was found that STING negatively modulated anti-fungal immunity in systemic fungal infection of the mouse model. Administration of the 18-aa peptide of STING at N-terminus improved the survival rate of mice when injected C. albicans intravenously.
The highlights of this study include: (1) STING-deficient mice exhibit enhanced anti-fungal immunity upon C. albicans infection. (2) STING translocates to the phagosomes upon C. albicans infection. (3) STING binds to Src via the N-terminal 18-aa motif to inhibit Syk-mediated signaling. (4) The N-terminal 18-aa peptide of STING improves host outcome toward fungal infection. This study was selected in Research Highlights by Nature Reviews Immunology (NRI), which was published on Jul. 10th, for its importance of revealing the negative regulation in response to fungal infection by STING.
Prof. Gao group focus on studying the mechanisms by which the immune signal transduction controls microbial infections. As the corresponding author, Prof. Gao has published high-profile journals including Nat Immunol, Nat Commun, J Exp Med, Cell Rep, PLOS Pathog. This work was supported by grants from the National Natural Science Foundation of China, the National key research and development program. This work was also supported by China Postdoctoral Science Foundation, and Future Scholar Program of Shandong University.
Article DOI：https://doi.org/10.1016/j.immuni.2023.06.002
NRI Research highlight：https://doi.org/10.1038/s41577-023-00916-3
