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P53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression.

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.

SUBMITTER: Ghosh M

PROVIDER: S-EPMC9993620 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Ghosh Monisankar M Saha Suchandrima S Li Jinyu J Montrose David C DC Martinez Luis A LA

Molecular cell 20230112 2

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 ...[more]

PMID: 36638783

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Project description:Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor capable of detecting microbial DNA and activating the adaptor protein stimulator of interferon genes (STING), leading to interferon (IFN) production and host antiviral responses. Cells exhibited reduced type I IFN production in response to cytosolic DNA in the absence of cGAS. Although the cGAS/STING-mediated DNA-sensing signal is crucial for host defense against many viruses, especially for DNA viruses, few viral components have been identified to specifically target this signaling pathway. Herpes simplex virus 1 (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. In the present study, we found that HSV-1 tegument protein UL41 was involved in counteracting the cGAS/STING-mediated DNA-sensing pathway. Our results showed that wild-type (WT) HSV-1 infection could inhibit immunostimulatory DNA-induced activation of the IFN signaling pathway compared with the UL41-null mutant virus (R2621), and ectopic expression of UL41 decreased cGAS/STING-mediated IFN-β promoter activation and IFN-β production. Further study indicated that UL41 reduced the accumulation of cGAS to abrogate host recognition of viral DNA. In addition, stable knockdown of cGAS facilitated the replication of R2621 but not WT HSV-1. For the first time, HSV-1 UL41 was demonstrated to evade the cGAS/STING-mediated DNA-sensing pathway by degrading cGAS via its RNase activity.IMPORTANCE HSV-1 is well known for its ability to evade host antiviral responses and establish a lifelong latent infection while triggering reactivation and lytic infection under stress. Currently, whether HSV-1 evades the cytosolic DNA sensing and signaling is still poorly understood. In the present study, we found that tegument protein UL41 targeted the cGAS/STING-mediated cellular DNA-sensing pathway by selectively degrading cGAS mRNA. Knockdown of endogenous cGAS could facilitate the replication of R2621 but not WT HSV-1. Furthermore, UL41 was shown for the first time to act directly on cGAS. Findings in this study could provide new insights into the host-virus interaction and help develop new approaches against HSV-1.

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P53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression.

Publications

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

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