SUMOylated PABPC1 Shields Mitophagy Genes Inside Stress Granules to Help Cells Survive

Cells under stress rapidly assemble membraneless cytoplasmic compartments called stress granules (SGs), which regulate mRNA fate and help cells survive hostile conditions. While SGs are known to sequester select mRNAs, the molecular logic governing which transcripts are protected — and why — has remained poorly understood. This Nature Communications study identifies a specific post-translational modification on PABPC1, a core SG scaffold protein, as the key sorting signal that links stress sensing to selective mRNA protection and mitophagy activation.

The authors demonstrate that PABPC1 undergoes robust SUMOylation — predominantly via SUMO1 — upon exposure to sodium arsenite (oxidative stress), heat shock, sorbitol (osmotic stress), and glucose starvation. SUMOylation peaked within 1–3 hours of arsenite treatment and resolved upon stress removal, precisely tracking SG assembly and disassembly as confirmed by co-immunofluorescence with SG marker G3BP1. The modification was validated through multiple orthogonal methods: Ni2+-NTA pulldown, denaturing immunoprecipitation in SENP1-knockout cells, and a prokaryotic in vitro SUMOylation assay in E. coli expressing GST-PABPC1 with the pT-E1E2S1 plasmid.

Using site-directed mutagenesis, the team mapped the primary SUMOylation site to lysine 512 (K512), which lies within the RNA recognition motif (RRM3) domain of PABPC1. A K512R substitution abolished SUMOylation, impaired SG formation, and dramatically reduced cancer cell viability under stress. Conversely, a phosphomimetic SUMO-fused PABPC1 construct rescued these deficits. Transcriptome-wide RNA sequencing and eCLIP-seq revealed that SUMOylated PABPC1 preferentially stabilizes mRNAs containing conserved U-rich elements (UREs) in their 3' UTRs — a distinct selectivity not shared by unmodified PABPC1.

Mechanistically, SUMOylated PABPC1 was found to directly interact with TIA1 via TIA1's SUMO-interacting motif (SIM). This PABPC1–SUMO–TIA1 ternary complex recruits U-rich mRNAs into SGs, protecting them from exosome-mediated degradation. Among the most prominently stabilized transcripts were FUNDC1 and BNIP3L, two critical receptors for mitophagy — the selective autophagic removal of damaged mitochondria. Blocking K512 SUMOylation reduced FUNDC1 and BNIP3L protein expression, impaired mitophagy flux (measured by LC3-II puncta, mitochondrial mass markers, and COX IV levels), and increased mitochondrial reactive oxygen species accumulation, ultimately sensitizing cells to stress-induced death.

Functionally, cancer cell lines with restored SUMOylated PABPC1 showed significantly enhanced survival under arsenite, chemotherapy, and nutrient deprivation conditions, while PABPC1-K512R-expressing cells exhibited markedly reduced clonogenic survival. These findings establish a direct molecular chain from stress sensing → PABPC1 K512 SUMOylation → SG-mediated U-rich mRNA stabilization → mitophagy gene upregulation → cellular homeostasis and survival. The study positions PABPC1 SUMOylation as a potential therapeutic vulnerability in cancers that rely on stress adaptation for chemoresistance, and more broadly illuminates how cells prioritize specific survival transcripts during stress.