PABPC1 SUMOylation enhances cell survival by promoting mitophagy through stabilizing U-rich mRNAs within stress granules

Caihu Huang, Jiayi Huang, Runhui Lu, Ari Jiazhuo Yu, Arno Shengzhuo Yu, Yingting Cao, Lian Li, Junya Li, Hongyan Li, Zihan Zhou, Yixin Zhang, Anan Xu, Ran Chen, Yanli Wang, Xian Zhao, Jian Huang, Yujie Fu (), Ming Xu (), Hailong Zhang () and Jianxiu Yu ()
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Caihu Huang: Shanghai Jiao Tong University School of Medicine
Jiayi Huang: Shanghai Jiao Tong University School of Medicine
Runhui Lu: Shanghai Jiao Tong University School of Medicine
Ari Jiazhuo Yu: University of California—Santa Barbara
Arno Shengzhuo Yu: University of California—Santa Barbara
Yingting Cao: Shanghai Jiao Tong University School of Medicine
Lian Li: Shanghai Jiao Tong University School of Medicine
Junya Li: Shanghai Jiao Tong University School of Medicine
Hongyan Li: Shanghai Jiao Tong University School of Medicine
Zihan Zhou: Shanghai Jiao Tong University School of Medicine
Yixin Zhang: Shanghai Jiao Tong University School of Medicine
Anan Xu: Shanghai Jiao Tong University School of Medicine
Ran Chen: Shanghai Jiao Tong University School of Medicine
Yanli Wang: Shanghai Jiao Tong University School of Medicine
Xian Zhao: Shanghai Jiao Tong University School of Medicine
Jian Huang: Shanghai Jiao Tong University School of Medicine
Yujie Fu: Shanghai Jiao Tong University School of Medicine
Ming Xu: Shanghai Jiao Tong University School of Medicine
Hailong Zhang: Sun Yat-sen University
Jianxiu Yu: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Stress granules (SGs) are cytoplasmic, membraneless organelles that modulate mRNA metabolism and cellular adaptation under stress, yet the mechanisms by which they regulate cancer cell survival remain unclear. Here, we identify Poly(A)-Binding Protein Cytoplasmic 1 (PABPC1), a core SG component, as stress-inducible SUMOylation target. Upon various stress conditions, SUMOylated PABPC1 promotes SG assembly and enhances cancer cell survival. Transcriptome-wide analysis reveals that SUMOylated PABPC1 selectively stabilizes mRNAs enriched in conserved U-rich elements. Mechanistically, SUMOylated PABPC1 interacts with RNA-binding protein TIA1 to form PABPC1–SUMO–TIA1 complex that recruits U-rich mRNAs into SGs, protecting them from degradation. This process facilitates the expression of U-rich genes, such as mitophagy-related genes FUNDC1, BNIP3L, thereby maintaining cellular homeostasis and promoting cell survival under adverse conditions. Our findings reveal that PABPC1 SUMOylation connects stress granule assembly with selective U-rich mRNA stabilization and mitophagy, promoting cancer cell stress adaptation.

Date: 2025
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DOI: 10.1038/s41467-025-62619-8

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