Regulation of cGAS-Mediated Immune Responses and Immunotherapy

Abstract

Early detection of infectious nucleic acids released from invading pathogens by the innate immune system is critical for immune defense. Detection of these nucleic acids by host immune sensors and regulation of DNA sensing pathways have been significant interests in the past years. Here, current understandings of evolutionarily conserved DNA sensing cyclic GMP-AMP (cGAMP) synthase (cGAS) are highlighted. Precise activation and tight regulation of cGAS are vital in appropriate innate immune responses, senescence, tumorigenesis and immunotherapy, and autoimmunity. Hence, substantial insights into cytosolic DNA sensing and immunotherapy of indispensable cytosolic sensors have been detailed to extend limited knowledge available thus far. This Review offers a critical, in-depth understanding of cGAS regulation, cytosolic DNA sensing, and currently established therapeutic approaches of essential cytosolic immune agents for improved human health.

Keywords: cGAS‐STING; cytosolic sensing; immunotherapy; innate immune regulation; tumorigenesis.

Figure 1

PRRs recognized PAMPs, evolutionarily conserved features derived from bacteria, fungi, parasites, and viruses, to avert pathogen invasion. PAMPs from invading microbes activate PRRs, including TLRs, RLRs, NLRs, and CLRs. Subsequently, PRRs trigger cGAS‐STING immune pathways, which lead to the induction of IFNs and pro‐inflammatory cytokines. PRRs: pattern‐recognition receptors; RLRs: RIG‐I‐like receptors; NLRs: nucleotide oligomerization and binding domain (NOD)‐like receptors; ALRs: AIM2‐like receptors; CLRs: C‐type lectin‐like receptors; PAMPs: pathogen‐associated molecular patterns.

Figure 2

Cytosolic nucleic acid sensors and recognition of innate immune pathways. Nucleic acids (i.e., ssRNA, dsRNA, and DNA) presented by viruses, bacteria, and impaired host cells are leaked and recognized by DNA sensors in the cytosol. During infection, foreign nucleic acids are recognized by RLRs, non‐RLRs, and cGAS, which lead to the induction of IFNs by adaptor proteins MAVS and STING, and transcription factors NF‐κB, IRF1, IRF3, IRF5, and IRF7. Pol III, polymerase III; LGP2, laboratory of genetics and physiology 2; RIG‐I, retinoic acid‐inducible gene I; MDA5, melanoma differentiation‐associated protein 5; IFIT, IFN‐induced protein with tetratricopeptide repeats; NOD2, nucleotide‐binding oligomerization domain 2; PKR, protein kinase R; AIM2, absent in melanoma 2; DNA‐PK, DNA‐dependent protein kinase; cGAS, cyclic GMP‐AMP synthase; ZBPI/DAI, Z‐DNA binding protein 1/DNA‐dependent activator of IFN regulatory factors; IFI16, IFN‐gamma inducible protein 16; MRE11, meiotic recombination 11 homolog A; Lsm14A, LSM14A mRNA processing body assembly factor; Ku70/80, Ku heterodimer; LRRFIP1, LRR binding FLII interacting protein 1; DDX41, DExD/H‐box helicase.

Figure 3

cGAS activation structure and orientation in cGAS‐DNA dimer complex. A) cGAS exists in the apo form in auto‐inhibited conformation (PDB code 4KB6), and detailed observation of the “zinc‐thumb.” Binding to the sugar‐phosphate spine of DNA results in the exposure of cGAS‐DNA composites and cGAS‐active catalytic sites by structural rearrangements for nucleotide binding and catalysis. DNA minor groove is the target drug delivery site employed for therapeutics. B) Ribbon representation of the side views of the cGAS model with marked domains and structures. (cyan α‐helices, green β‐strands; PDB code 4JLX). C) cGAS dimers engage DNA along with zinc (Zn²⁺)‐thumb dimerization elements (PDB code 5N6I). The interchanging “head‐to‐head” or “tail‐to‐tail” assemblage leads to ladder‐like cGAS association over quasi‐continuous DNA in the crystal lattice.

Figure 4

Innate immune regulation of cGAS‐STING‐mediated immune pathways by the host or viral elements. Regulation of cGAS‐mediated immune pathways include i) neutralization of viral nucleic acids, capsid, and proteins by host elements, ii) inhibition of DNA binding to cGAS by viral proteins, iii) inhibition of cGAS activity, cGAS downstream signaling, and its expression by viral‐encoded proteins, phosphorylation, methylation and autophagy, iv) inhibition, blockade, and activity prevention of cGAMP, STING‐TBK1, IRF3/7, NF‐κB, ISGs, IFNs, JAK/STAT signaling pathway, and other cytokines by several viral‐encoded proteins and host elements. Additionally, cGAS is indispensable for cGAS‐STING‐mediated antitumor immunity by superior cross‐presentation of tumor‐related antigens to CD8 T‐cells or CTLs. SOCS, suppressor of cytokine signaling; IFNAR, IFN‐α/β receptor; CTL, cytotoxic T‐cell; CD, cluster of differentiation; Ub, ubiquitin.

Figure 5

cGAS is essential in cellular senescence and SASP regulation. A) Senescence is triggered by various cellular stresses and cell damage, succeeding the accrual of cytosolic DNA. Consequently, cGAS recognizes DNA and triggers the cGAS–STING pathway to produce SASP factors and induce autocrine and paracrine senescence. Anti‐inflammatory cytokines mediate the clearance of tumor cells by immune cells, whereas pro‐inflammatory cytokines enhance tumorigenesis. B) The processes that lead to cellular senescence, age‐associated diseases, and fundamental aging mechanisms. Interacting with these processes may provide possible therapeutic measures to improve human health.