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

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• TP53 (p53) tumor suppression involves complex mechanisms.
• p53's role in modulating immune functions for tumor suppression requires further elucidation.
• The precise molecular pathways linking p53 to immune modulation are not fully understood.

Purpose of the Study:

• To investigate the mechanistic basis of p53-mediated tumor suppression via immune system modulation.
• To identify the molecular players involved in p53's non-cell-autonomous tumor suppressor functions.
• To elucidate the role of cytosolic DNA sensing in p53's anti-tumor activities.

Main Methods:

• Investigated p53-mediated degradation of TREX1 using molecular biology techniques.
• Assessed the role of TRIM24 in p53-induced TREX1 degradation.
• Utilized cGAS/STING pathway activation assays and knockout models to study downstream effects.
• Examined the impact of TREX1 modulation and cGAS/STING pathway activity on p53's tumor suppressor functions.

Main Results:

• p53 promotes the degradation of the DNA exonuclease TREX1 via the ubiquitin ligase TRIM24.
• TREX1 degradation leads to cytosolic double-stranded DNA (dsDNA) accumulation.
• Accumulated cytosolic dsDNA activates the cGAS/STING pathway, inducing type I interferons (IFNB1).
• TREX1 overexpression inhibits p53-mediated cGAS/STING activation.
• Loss of cGAS/STING signaling compromises p53's tumor suppressor activities.

Conclusions:

• p53 utilizes the cGAS/STING innate immune pathway to suppress tumors.
• This pathway is essential for both cell-intrinsic and cell-extrinsic tumor suppressor activities of p53.
• p53-mediated TREX1 degradation is a key step in activating the cGAS/STING pathway for tumor suppression.