Cited by 167interferon and immune responsesCancer-related Molecular PathwaysTGF-β signaling in diseases

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p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression

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Ghosh, Monisankar, Saha, Suchandrima, Li, Jinyu, Montrose, David C., Martinez, Luis A.·2023·Molecular Cell

DOI 10.1016/j.molcel.2022.12.023PMC PMC9993620

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Abstract

Tumor suppression by TP53 involves cell-autonomous and non-cell-autonomous mechanisms. TP53 can suppress tumor growth by modulating immune system functions; however, the mechanistic basis for this activity is not well understood. We report that p53 promotes the degradation of the DNA exonuclease TREX1, resulting in cytosolic dsDNA accumulation. We demonstrate that p53 requires the ubiquitin ligase TRIM24 to induce TREX1 degradation. The cytosolic DNA accumulation resulting from TREX1 degradation activates the cytosolic DNA-sensing cGAS/STING pathway, resulting in induction of type I interferons. TREX1 overexpression sufficed to block p53 activation of the cGAS/STING pathway. p53-mediated induction of type I interferon (IFNB1) is suppressed by cGAS/STING knockout, and p53's tumor suppressor activities are compromised by the loss of signaling through the cGAS/STING pathway. Thus, our study reveals that p53 utilizes the cGAS/STING innate immune system pathway for both cell-intrinsic and cell-extrinsic tumor suppressor activities.

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Background
STING exerts antiviral innate immune response by activating pentose phosphate pathway
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Background
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Authors: Ghosh, M., Saha, S., Li, J., Montrose, D. C., & Martinez, L. A.
Affiliations: Stony Brook University (US)
Stony Brook Medicine (US)
Corresponding author: Martinez, Luis A.
ORCID: Ghosh, Monisankar
Saha, Suchandrima
Li, Jinyu
Montrose, David C.
Martinez, Luis A.
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2023-01
Volume: 83
Issue: 2
Pages: 266-280.e6
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2022.12.023
PMC: PMC9993620
OpenAlex: W4315705275
Cited by: 166
References: 60
Citations by year: 2026: 48 · 2025: 54 · 2024: 37 · 2023: 27
FWCI: 18.10
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Molecular Cell (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Stony Brook University
National Institutes of Health
National Cancer Institute (K22CA226033, R01CA166974)
Topics: Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords: TP53, p53, cGAS-STING pathway, cytosolic DNA sensing, TRIM24, type I interferon, IFNB1, tumor suppression, innate immunity, double-stranded DNA, ubiquitin ligase
MeSH terms: STING Protein, DNA, Immunity, Innate, Interferon Type I, Membrane Proteins, Nucleotidyltransferases, Signal Transduction, Tumor Suppressor Protein p53

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p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression

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