Distinct roles of IDR and CCD domains control PABPN1 aggregation and enable therapeutic rescue

Abstract PABPN1 is a multifunctional protein whose expression is tightly regulated to maintain cellular homeostasis. PABPN1 dysregulation contributes to both common acquired diseases, such as bladder cancer, and rare inherited disorders, including oculopharyngeal muscular dystrophy (OPMD). In OPMD, PABPN1 forms insoluble aggregates that reduces its functional levels, leading to genome-wide shifts in alternative polyadenylation (APA) at 3′-UTRs, and disruption of mRNA metabolism, including nuclear export and translation. OPMD is caused by a short alanine expansion at the N-terminus of PABPN1 within an intrinsically disordered region (IDR) followed by a coiled-coil domain (CCD). How these domains contribute to PABPN1 function and aggregation remains unclear. Here, we show that the N-terminal IDR promotes aggregation and modulates protein–protein interactions with longer IDRs suppressing interaction between PABPN1 and its binding partners. We further demonstrate that the CCD has dual functions: its N-terminal domain dictates PABPN1 stability, whereas its C-terminal domain enhances the PABPN1 interactome. We identified a naturally occurring variant lacking exon 1 encoding to the IDR and the CCD N-terminal domain (named trPAB). That variant forms a stable, non-aggregating protein isoform. Interactome analysis and structural modeling indicate improved molecular function by restoring PABPN1 activity, APA profiles, and cellular phenotypes in OPMD and bladder cancer models. Importantly, delivery of trPAB via Adeno-associated viral vector in an OPMD mouse model improves muscle histopathology, supporting its potential as a therapeutic strategy.