| NUP98 is a GLFG-repeat–containing nucleoporin generated from a precursor that is proteolytically cleaved to yield NUP98 and NUP96, two nucleoplasmically oriented components of the nuclear pore complex that contribute to nucleocytoplasmic transport, nuclear pore biogenesis, and gene regulation. The N‑terminal half of NUP98 is rich in phenylalanine–glycine (FG) and Gly–Leu–Phe–Gly (GLFG) repeats that form flexible, intrinsically disordered domains extending into the transport channel, while the C‑terminal region contains a structured pore-targeting domain that binds directly to other scaffold nucleoporins such as NUP96 and the cytoplasmic NUP88, positioning NUP98 on both the nuclear and cytoplasmic faces of the pore. This architecture allows NUP98 to function as a mobile FG nucleoporin that shuttles between the NPC and intranuclear foci and acts as a docking platform and cofactor for karyopherin-dependent transport, including Crm1‑mediated nuclear protein export and importin‑4–mediated nuclear protein import, where its FG repeat region binds Crm1 or importin-4 in a RanGTP-dependent manner and facilitates efficient receptor–cargo passage across the pore. Antibody blockade or depletion of NUP98 selectively inhibits export of bulk mRNA and Crm1‑dependent protein cargoes, and mutations that disrupt FG motifs attenuate its binding to export and import receptors, demonstrating that NUP98 is required for normal flux of RNAs and proteins through the NPC and for maintaining transport selectivity and directionality. NUP98 also contributes to NPC assembly and quality control; vertebrate NUP98 is essential for pore formation, and recent work identifies a checkpoint function for NUP98 in nuclear pore biogenesis, where defects in NUP98 regulation alter NPC stoichiometry and lead to transport imbalances that impact cell-cycle progression and proteostasis. NUP98 also engages directly in gene expression control by associating with chromatin at promoters and regulatory regions and by interacting with transcriptional coactivators such as CBP/p300 and with the RNA helicase DHX9, thereby modulating transcription of developmental and cell-cycle genes and linking NPC composition to nuclear gene expression programs. The NUP98 gene resides within a tumor-suppressor region at 11p15.5 and is a frequent target of chromosomal translocations in acute myeloid leukemia and related hematologic malignancies, where NUP98 fuses with homeobox proteins (for example HOXA9) or histone methyltransferases (for example NSD1), generating chimeric transcription factors that aberrantly activate HOX and other developmental genes, disrupt normal differentiation, and drive leukemogenesis while often leaving one endogenous NUP98 allele intact to support essential pore functions. |
