The inner nuclear membrane (INM) represents a specialized subdomain of the endoplasmic reticulum (ER). The INM houses a unique set of integral membrane proteins that perform key functions in the organization of intranuclear architecture, control of gene expression and coupling of the nucleus to the cytoskeleton. However, the molecular mechanism of membrane protein sorting from the ER to the INM has remained enigmatic. Recently, novel approaches combining visual kinetic assays and computational modeling were used to define the requirements of trafficking to the INM in human cells. These studies reveal that nuclear retention, diffusional mobility in the ER as well as the number and architecture of NPCs are major determinants of INM targeting, collectively lending support to a diffusion-retention-based mechanism.
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