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 ac-tivity 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 overexpres-sion 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.

Automated summary

Tumor suppression by TP53 involves both cell-autonomous and non-cell-autonomous mechanisms. This study reveals that p53 promotes the degradation of TREX1, leading to cytosolic dsDNA accumulation and activation of the cGAS/STING pathway, resulting in induction of type I interferons. The activation of the cGAS/STING pathway is crucial for p53's tumor suppressor activities.