Phase separation in cGAS-STING signaling

doi:10.1007/s11684-023-1026-6

Front. Med.

2023, Vol. 17

Issue (5) : 855-866 https://doi.org/10.1007/s11684-023-1026-6

REVIEW

Phase separation in cGAS-STING signaling

Quanjin Li(

), Pu Gao(

)

CAS Key Laboratory of Infection and Immunity, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China

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Abstract

Biomolecular condensates formed by phase separation are widespread and play critical roles in many physiological and pathological processes. cGAS-STING signaling functions to detect aberrant DNA signals to initiate anti-infection defense and antitumor immunity. At the same time, cGAS-STING signaling must be carefully regulated to maintain immune homeostasis. Interestingly, exciting recent studies have reported that biomolecular phase separation exists and plays important roles in different steps of cGAS-STING signaling, including cGAS condensates, STING condensates, and IRF3 condensates. In addition, several intracellular and extracellular factors have been proposed to modulate the condensates in cGAS-STING signaling. These studies reveal novel activation and regulation mechanisms of cGAS-STING signaling and provide new opportunities for drug discovery. Here, we summarize recent advances in the phase separation of cGAS-STING signaling and the development of potential drugs targeting these innate immune condensates.

Keywords biomolecular condensates phase separation cGAS-STING pathway cGAS STING cGAMP interferon

Corresponding Author(s): Quanjin Li,Pu Gao

Just Accepted Date: 28 September 2023 Online First Date: 31 October 2023 Issue Date: 07 December 2023

Cite this article:

Quanjin Li,Pu Gao. Phase separation in cGAS-STING signaling[J]. Front. Med., 2023, 17(5): 855-866.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1026-6
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I5/855

Fig.1 Brief research history of the discovery of key components and related condensates in cGAS-STING signaling. (Note: this is an oversimplified research history with a focused perspective, and many other important contributions to this pathway are not listed here.)

Fig.2 Model of phase separation in cGAS-STING signaling. (a) Aberrant DNA from pathogens or the host induces cGAS to form cGAS-DNA condensates, which contribute to promote cGAS activation and suppress negative regulation mediated by TREX1 and BAF. Positive regulators such as Ku proteins, PCBP1, ZYG11B, zinc ions and streptavidin promote cGAS-DNA phase separation. Negative regulators such as PCBP2 and oleic acid suppress cGAS-DNA phase separation. (b) USP15 forms condensates with cGAS to promote cGAS-DNA phase separation. (c) G3BP1 forms condensates with cGAS to promote cGAS-DNA phase separation. (d) RNA forms condensates with cGAS to promote cGAS-DNA phase separation. (e) Spermine forms condensates with DNA to promote cGAS-DNA phase separation. (f) ORF52/VP22-type tegument proteins form condensates with DNA to disrupt cGAS-DNA phase separation. (g) SARS2-NP forms N-DNA-G3BP1 condensates to restrict the formation of cGAS-G3BP1 condensates. (h) Excessive cGAMP induces the formation of STING-cGAMP condensates that separate STING and TBK1 from IRF3 to suppress innate immune signaling. (i) IRF3 forms condensates with ISREs to recruit transcription factors and co-activators, thereby promoting IFN-I expression. (j) Activated IRF3 interacts with NF2m to form NF2m condensates where TBK1 and RACK1-PP2A complex are recruited and RACK1-PP2A complex dephosphorylates TBK1 to suppress innate immune signaling. (k) STING forms liquid-like condensates with PC7A to activate innate immune signaling.

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