Unraveling the Diversity of RANBP2: Protein Isoforms and Implications for Cellular Function and Human Disease

RANBP2 (also known as Nup358) is the largest nucleoporin of the nuclear pore complex (NPC), where it constitutes the main component of the cytoplasmic filaments and regulates nucleocytoplasmic transport. In addition to its NPC-associated functions, RANBP2 also localizes in the endoplasmic reticulum (ER) at annulate lamellae (AL), at mitochondria-ER junctions, and at kinetochores during mitosis, where it contributes to multiple cellular processes including metabolism and mitotic progression. Although most studies focus on the canonical full-length protein (∼358 kDa in humans), multiple smaller bands have been detected across species, suggesting the existence of alternative isoforms. Here, we review all predicted and experimentally supported RANBP2 transcript variants, summarize their structural features and discuss their possible origins, including alternative splicing, genomic recombination and proteolysis. We examine how isoform-specific changes, such as loss of the zinc finger domain, Ran-binding domains, E3 SUMO ligase, or the cyclophilin-like domain, could alter RANBP2's cellular functions. We also consider evidence for cell-type specific and developmentally regulated expression from non-human models, and evaluate the potential relevance of RANBP2 isoforms in viral infections and neurological disease. By compiling genomic, proteomic, and functional data, this review highlights the need for isoform-resolved approaches to fully understand RANBP2 biology and its contribution to human disease.