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Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping, swallowing difficulties, and proximal limb weakness. The autosomal dominant form of this disease is caused by the expansion of a polyalanine stretch from 10 to 12--17 alanines in the N-terminus of PABPN1. Mutated PABPN1 (mPABPN1) is able to induce the formation of filamentous intranuclear inclusions that are the pathological hallmark of OPMD. PABPN1 is predominantly localized to the nucleus, binds RNA poly(A) tail, forms oliogmers, and is involved in polyadenylation. In this study we first demonstrated that oligomerization of PABPN1 is mediated by two potential oligomerization domains (OD), while inactivating oligomerization of mPABPN1 by deletions of 6--8 residues in either of the ODs prevents intranuclear protein aggregation. Expression of mPABPN1 in COS-7 cells is associated with cell death, whereas preventing nuclear protein aggregation by inactivating oligomerization of mPABPN1 significantly reduces cell death. We then identified two PABPN1 interacting proteins, hnRNP A1 and A/B, using a yeast two-hybrid library screen. The interaction between PABPN1 and hnRNP A1 or A/B was confirmed by GST pull-down and co-immunoprecipitation assays. When coexpressed with mPABPN1 in COS-7 cells, predominantly nuclear localized hnRNP A1 and A/B co-localize with mPABPN1 to the insoluble intranuclear aggregates. Patient studies showed that hnRNP A1 is sequestered in OPMD nuclear inclusions. We finally found a nuclear localization signal (NLS) in PABPN1 that is not homologous to any known NLSs. The 18 amino acids 289RGRVYRGRARATSWYSPY 306 in PABPN1 are necessary and sufficient for nuclear translocation. Attaching this sequence to cytoplasmic protein PKM2 completely re-localizes it to the nucleus. Alanine-scanning mutagenesis analysis showed that the last 9 residues 298RATSWYSPY306 are crucial to the function as an NLS. Our studies showed that mPABPN1 induced intran