Breaching the nuclear envelope in development and disease

Abstract

In eukaryotic cells the nuclear genome is enclosed by the nuclear envelope (NE). In metazoans, the NE breaks down in mitosis and it has been assumed that the physical barrier separating nucleoplasm and cytoplasm remains intact during the rest of the cell cycle and cell differentiation. However, recent studies suggest that nonmitotic NE remodeling plays a critical role in development, virus infection, laminopathies, and cancer. Although the mechanisms underlying these NE restructuring events are currently being defined, one common theme is activation of protein kinase C family members in the interphase nucleus to disrupt the nuclear lamina, demonstrating the importance of the lamina in maintaining nuclear integrity.

Figure 1.

Nuclear envelope budding of export complexes. (A) Herpes virus capsids bind to viral proteins at the INM that also recruit PKC. Viral capsids then bud through the envelope at sites of lamina disorganization (gray) and are released into the cytoplasm. (B) mRNP export in differentiating muscle cells also requires disorganization of the nuclear lamina by PKC. mRNPs interact with the INM at sites of lamina disorganization and bud into the perinuclear space with the help of torsinA. The perinuclear vesicle fuses with the ONM and the mRNP is released into the cytoplasm.

Figure 2.

Nuclear envelope rupturing and collapse. (A) Association of parvovirus capsids with the ONM causes breakdown of first the outer and then the inner nuclear membranes. Activation of PKC and Cdk kinases in the nucleus during this time forms large gaps in the lamina, allowing the capsids to enter the nucleoplasm and causing a loss of nuclear integrity. (B) When lamina organization is disrupted by changes in lamina proteins, patches of weak membrane form and chromatin can herniate. This membrane can undergo multiple rounds of NE rupturing and repair, causing mislocalization and entrapment of cytosolic and nuclear components. (C) Micronuclei have a high probability of NE rupturing but fail to undergo NE repair, causing a persistent loss of nuclear integrity. After rupturing, the chromatin forms aberrant associations with ER tubules in a process called NE collapse.

Figure 3.

Nuclear envelope fusion. (A) An early step in interphase nuclear pore assembly is the formation of a channel through the NE by fusion of the inner and outer nuclear membranes. Membrane-associated proteins are thought to bend the membranes toward each other and stabilize the channel before nuclear pore assembly. (B) During fertilization and early embryonic divisions, multiple nuclei can form and must fuse into a mononucleus. Although the nuclear membranes are part of the same endomembrane system, specific proteins, including brambleberry, are required to initiate fusion. Full fusion requires mixing of the outer and inner nuclear membranes and, likely, disorganization of the lamina to expand the fusion pore.