p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression
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 TRE...
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Veröffentlicht in: | Molecular cell 2023-01, Vol.83 (2), p.266-280.e6 |
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Zusammenfassung: | 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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•Wild-type p53 (WTp53) activates the cytosolic DNA-sensing cGAS/STING pathway•WTp53 requires TRIM24 to promote TREX1 degradation•TREX1 degradation causes cytosolic DNA accumulation and activation of cGAS/STING•Loss of cGAS or STING compromises WTp53’s tumor suppressor activity
Ghosh et al. report that the tumor suppressor, TP53, activates the innate immune response to suppress tumor growth. TP53 promotes the degradation of the cytosolic DNA exonuclease TREX1, resulting in cytoplasmic DNA accumulation and activation of the cGAS/STING pathway. The absence of cGAS or STING compromises p53’s tumor suppressor activity. |
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ISSN: | 1097-2765 1097-4164 |
DOI: | 10.1016/j.molcel.2022.12.023 |