Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Apr 10:15:1356369.
doi: 10.3389/fimmu.2024.1356369. eCollection 2024.

The interplay between autophagy and cGAS-STING signaling and its implications for cancer

Maximilian Schmid #  1   2   3   4 , Patrick Fischer #  1   2   3   4 , Magdalena Engl  1   2   4   5 , Joachim Widder  1   2 , Sylvia Kerschbaum-Gruber  1   2   3 , Dea Slade  1   2   3   4
Affiliations
Review

The interplay between autophagy and cGAS-STING signaling and its implications for cancer

Maximilian Schmid et al. Front Immunol. .

Abstract

Autophagy is an intracellular process that targets various cargos for degradation, including members of the cGAS-STING signaling cascade. cGAS-STING senses cytosolic double-stranded DNA and triggers an innate immune response through type I interferons. Emerging evidence suggests that autophagy plays a crucial role in regulating and fine-tuning cGAS-STING signaling. Reciprocally, cGAS-STING pathway members can actively induce canonical as well as various non-canonical forms of autophagy, establishing a regulatory network of feedback mechanisms that alter both the cGAS-STING and the autophagic pathway. The crosstalk between autophagy and the cGAS-STING pathway impacts a wide variety of cellular processes such as protection against pathogenic infections as well as signaling in neurodegenerative disease, autoinflammatory disease and cancer. Here we provide a comprehensive overview of the mechanisms involved in autophagy and cGAS-STING signaling, with a specific focus on the interactions between the two pathways and their importance for cancer.

Keywords: autophagy; cGAS/STING signaling; cancer; innate immunity; radiotherapy.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The mechanism of autophagosome biogenesis. 1) Upon starvation, mTORC1 dissociates from ULK1, which is then activated via autophosphorylation and phosphorylates ATG13 and FIP200. 2) ULK1 is recruited to the phagophore assembly site together with ATG9-positive vesicles. ULK1 phosphorylates the PI3K complex, inducing the production of PI3P. PI3P leads to the recruitment of WIPI2. 3) The ATG16L1 complex is recruited to the growing autophagosome via WIPI2 and conjugates ATG8-family proteins such as LC3 to PE. Lipid influx is controlled via ATG2, which acts as a channel funneling lipids from donor compartments. Autophagosome closure is mediated by the ESCRT complex. Membrane contacts are dissolved via VMP1-mediated changes in local Ca2+ concentration. 4) Fully formed autophagosomes travel to the lysosome and undergo fusion mediated by SNARE proteins, tethering factors and RABs. Cargo is then degraded by lysosomal hydrolases.
Figure 2
Figure 2
The cGAS-STING pathway is directly connected to autophagy. cGAS-STING signaling is an innate immune pathway, responsible for the production of type I IFNs. Extracellular stressors such as genotoxic stress or viral infection as well as genomic instability can lead to the appearance of dsDNA in the cytosol. cGAS is activated upon binding dsDNA, which leads to the production of the secondary messenger cGAMP. cGAMP then activates STING, located at the ER, inducing its oligomerization and translocation to the Golgi via the ERGIC. Alternatively, cGAMP can also trigger the activation of STING in neighbouring cells via intercellular transport mediated by gap junctions. At the Golgi, STING induces the phosphorylation of TBK1 and ultimately IRF3 leading to its translocation to the nucleus where phosphorylated IRF3 drives the transcription of type I IFNs. Each distinct step of the cGAS-STING pathway is interconnected with autophagy. For example, STING, upon activation, leads to the formation of autophagosomes at the ERGIC in a WIPI2-dependent manner. This acts as a negative feedback loop by degrading dsDNA and other members of the pathway, such as cGAS or IRF3. Additionally, microautophagy is responsible for the final termination of STING signaling in an ESCRT-dependent manner.
Figure 3
Figure 3
Autophagy as a negative regulator of cGAS. cGAS is a cytosolic sensor for long cytosolic dsDNA fragments. Binding to long dsDNA fragments leads to productive cGAS-STING signaling culminating in the production of type I IFNs. Conversely, binding of small cytosolic dsDNA (<45bp) promotes binding of cGAS to Beclin-1, thereby reducing the interaction of Beclin-1 with Rubicon, a negative regulator of autophagy. This gives rise to the production of PI3P and the formation of autophagosomes allowing degradation of cytosolic dsDNA and negatively impacting cGAS activation. cGAS can also act as a selective autophagy receptor for micronuclei causing their ultimate degradation and thereby prohibiting them from releasing DNA into the cytosol. Finally, K48-linked ubiquitination of cGAS promotes selective p62-dependent autophagic degradation of cGAS, limiting the available amount of activatable cGAS.
Figure 4
Figure 4
STING signaling is linked to autophagy. STING directly induces the formation of autophagosomes at the ERGIC in a WIPI2-dependent manner utilizing the ERGIC as a membrane source. This process is independent of “canonical” upstream autophagic machinery such as ULK1 or VPS34. However, STING itself is not degraded this way but rather by microautophagy where it is packaged into clathrin-coated vesicles from the Golgi by AP-1. These vesicles are directly taken up by lysosomes thereby terminating STING signaling. Alternatively, upon activation by cGAMP, STING can be transported to neighbouring cells inside non-canonical RAB22A-dependent autophagosomes that fuse with endosomes. The emerging new vesicle can inactivate Rab7, thereby escaping lysosomal degradation and allowing STING pathway activation in surrounding tissues.
Figure 5
Figure 5
TBK1 regulates different types of autophagy. 1) mTORC1: TBK1 can positively and negatively affect autophagic flux via direct or indirect regulation of mTORC1. Phosphorylation of RAPTOR by TBK1 decreases the activity of mTORC1 and promotes autophagy. In addition, TBK1 can directly phosphorylate mTOR, which increases mTORC1 activity and decreases autophagic flux. 2) AMPK: AMPK can enhance TBK1 activity via ULK1-mediated phosphorylation of TBK1. High levels of active TBK1, however, negatively regulate AMPK, thus creating a negative feedback loop that can negatively affect autophagic flux. 3) Mitophagy: During PINK1-PARKIN-mediated mitophagy, OPTN and NDP52 redundantly activate TBK1, which in turn phosphorylates OPTN and NDP52 to ensure their retention at damaged mitochondria and facilitate the recruitment of ATG8 family proteins. In addition, TBK1-mediated phosphorylation enables spatial proximity to the autophagic machinery by facilitating the binding of NDP52 to the FIP200/ULK1 complex. During OPTN-induced autophagy, TBK1 can take over the functions of the ULK1 complex and directly interact with the PI3K complex to drive mitophagy. Moreover, by phosphorylating RAB7A, TBK1 enables recruitment of ATG9-positive vesicles to damaged mitochondria. 4) Xenophagy: Gal8 recognizes exposed glycans and recruits NDP52. Subsequently, TBK1 is recruited via the two adapter proteins NAP1 and SINTBAD leading to the formation of a NDP52-ULK1-TBK1 super complex, which is essential for phagophore formation. In addition, TBK1 directly phosphorylates the selective autophagy receptors p62 and OPTN, which are crucial for autophagic clearance of ubiquitin-coated bacteria.
Figure 6
Figure 6
Multiple modes of autophagy negatively regulate TBK1. ATG4B directly associates with TBK1 and acts as an adapter mediating the direct LIR-dependent interaction between the ATG8 family protein GABARAP and TBK1 leading to TBK1 degradation via the autophagosome. The E3 ubiquitin ligase NEDD4 is responsible for the deposition of K27-linked polyubiquitin chains on TBK1, which can be recognized by NDP52 causing selective degradation of TBK1. Conversely, TBK1 can also be degraded by chaperone-mediated autophagy via TBK1 CMA motif that is recognized by the CMA adapter proteins HSPA8 and USP19.
Figure 7
Figure 7
IRF3 is selectively degraded via the autophagic cargo receptors p62 and NDP52. The deubiquitinase OTUD7B removes ubiquitin chains from p62, thereby allowing it to more efficiently oligomerize. This allows for tighter association between p62 and IRF3, causing selective autophagic degradation of IRF3. Autophagic degradation of IRF3 is further promoted by the selective cargo receptor NDP52, which recognizes K27-linked polyubiquitin chains on IRF3, thereby inducing its autophagic degradation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. (2018) 19:349–64. doi: 10.1038/s41580-018-0003-4 - DOI - PubMed
    1. Hansen M, Rubinsztein DC, Walker DW. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol. (2018) 19:579–93. doi: 10.1038/s41580-018-0033-y - DOI - PMC - PubMed
    1. Vargas JNS, Hamasaki M, Kawabata T, Youle RJ, Yoshimori T. The mechanisms and roles of selective autophagy in mammals. Nat Rev Mol Cell Biol. (2022) 24:167–85. doi: 10.1038/s41580-022-00542-2 - DOI - PubMed
    1. Ponpuak M, Mandell MA, Kimura T, Chauhan S, Cleyrat C, Deretic V, et al. . Secretory autophagy. Curr Opin Cell Biol. (2015) 35:106–16. doi: 10.1016/j.ceb.2015.04.016 - DOI - PMC - PubMed
    1. Dupont N, Jiang S, Pilli M, Ornatowski W, Bhattacharya D, Deretic V, et al. . Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1β. EMBO J. (2011) 30:4701–11. doi: 10.1038/emboj.2011.398 - DOI - PMC - PubMed

Publication types

Grants and funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.