The nucleus: keeping it together by keeping it apart

It has been postulated that the segregation of nucleus and cytoplasm supported the development of increased organismal complexity. For example, separating transcription and translation allows for mRNA splicing, while the sequestration of genomic DNA supports the innate immune system’s ability to equate cytoplasmic DNA with pathogens. Consistent with the importance of nucleocytoplasmic compartmentalization in a broad array of cellular processes, defects in maintaining discrete nuclear and cytoplasmic compartments, either due to loss of nuclear pore complex integrity, disrupted nuclear transport or ruptures of the nuclear envelope, lead to cellular dysfunction, cell death and disease. Here, we discuss recent insights into how loss of compartmentalization can arise as well as the consequences for cellular and organismal homeostasis.