Predicted mechanism of interphase eukaryotic nuclear pore insertion predicted by the inside-out model. (A) The nuclear envelope is held together through LINC complexes. (B, C) Folds in the inner membrane of the envelope recruit the outer ring of the nuclear pore, composed of proteins with COPII-like domains, to generate a small extranuclear bleb, which is stabilized via the assembly of the complete nuclear pore complex. (D) The nuclear pore complex, together with LINC complexes, generates a tight membrane fold at the bud neck. (E) The nascent bleb is connected to the rest of the cytoplasm by active bleb-bleb fusion, ensuring cytoplasmic continuity. Note that in this model the continuity of the perinuclear space and the endoplasmic reticulum (ER) is a simple consequence of the mechanism of bleb generation. The relative rates at which bleb expansion (A-D) and the fusion of cytoplasmic compartments (E) occur will determine the size of individual cytoplasmic blebs and the extent of cytoplasmic compartmentalization. Thus, if the compartment fusion reaction (D, E) is induced immediately, no enlarged blebs would be seen.