CHK2-USP37 axis stabilizes FOXO4 to sustain senescence and evade apoptosis
Jiahui Sun1, Anke Geng1, Zhiwei Song1
1Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Abstract:
Cellular senescence, a state of permanent cell cycle arrest, contributes to tissue dysfunction and aging through the accumulation of apoptosis-resistant senescent cells. Although the transcription factor FOXO4 is known to enhance senescent cell survival, the mechanisms regulating its stability have remained unclear. Here, we identify a DNA damage response (DDR)-driven CHK2-USP37-FOXO4 axis essential for maintaining the apoptotic resistance of senescent cells. We demonstrate that FOXO4 protein stability is elevated in stress-induced senescent cells, resulting from reduced ubiquitin-proteasomal degradation. A deubiquitinase screen identified USP37 as the key enzyme stabilizing FOXO4 through direct interaction and removal of K48-linked polyubiquitin chains. Depletion of USP37 destabilizes FOXO4 and sensitizes senescent cells to apoptosis. Mechanistically, persistent DDR signaling during senescence activates CHK2, which phosphorylates USP37 at Thr589, thereby enhancing its binding to FOXO4. Importantly, ablation of USP37 in senescent cells increases the rate of apoptosis, a phenotype that is rescued by FOXO4 reexpression. Together, our work unveils USP37 as a CHK2-regulated stabilizer of FOXO4 that maintains the apoptotic resistance of senescent cells, suggesting the CHK2-USP37-FOXO4 axis as a therapeutic target for age-related pathologies.
Insights
Cellular senescence involves apoptosis-resistant cells. A DNA damage response (DDR) pathway involving CHK2, USP37, and FOXO4 stabilizes these cells, but targeting this axis may treat age-related diseases.
Area of Science:
- Cellular biology
- Molecular mechanisms of aging
- DNA damage response
Background:
- Cellular senescence contributes to aging and tissue dysfunction via apoptosis-resistant cells.
- The transcription factor FOXO4 promotes senescent cell survival, but its stabilization mechanisms are unknown.
Purpose of the Study:
- To elucidate the regulatory mechanisms of FOXO4 stability in senescent cells.
- To identify therapeutic targets for age-related pathologies by investigating the CHK2-USP37-FOXO4 axis.
Main Methods:
- Utilized a deubiquitinase screen to identify enzymes stabilizing FOXO4.
- Investigated the interaction and functional consequences of USP37 depletion in senescent cells.
- Examined the role of CHK2-mediated phosphorylation of USP37 in FOXO4 stabilization.
Main Results:
- Identified USP37 as a key deubiquitinase that stabilizes FOXO4 by removing K48-linked polyubiquitin chains.
- Depletion of USP37 destabilized FOXO4, increased senescent cell apoptosis, and this effect was rescued by FOXO4 reexpression.
- Discovered that CHK2 phosphorylates USP37, enhancing its binding to FOXO4 and promoting apoptotic resistance in senescent cells.
Conclusions:
- Unveiled a novel DNA damage response (DDR)-driven axis (CHK2-USP37-FOXO4) essential for maintaining senescent cell survival.
- USP37 acts as a CHK2-regulated stabilizer of FOXO4, crucial for apoptotic resistance in senescent cells.
- The CHK2-USP37-FOXO4 pathway represents a potential therapeutic target for age-related diseases.
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