PABPC1 SUMOylation enhances cell survival by promoting mitophagy through stabilizing U-rich mRNAs within stress granules (4sU-Seq)

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.