Patrolling the nucleus: inner nuclear membrane-associated degradation

Protein quality control and transport are important for the integrity of organelles such as the endoplasmic reticulum, but it is largely unknown how protein homeostasis is regulated at the nuclear envelope (NE) despite the connection between NE protein function and human disease. Elucidating mechanisms that regulate the NE proteome is key to understanding nuclear processes such as gene expression, DNA replication and repair as NE components, particularly proteins at the inner nuclear membrane (INM), are involved in the maintenance of nuclear structure, nuclear positioning and chromosome organization. Nuclear pore complexes control the entry and exit of proteins in and out of the nucleus, restricting movement across the nuclear membrane based on protein size, or the size of the extraluminal-facing domain of a transmembrane protein, providing one level of INM proteome regulation. Research in budding yeast has identified a protein quality control system that targets mislocalized and misfolded proteins at the INM. Here, we review what is known about INM-associated degradation, including recent evidence suggesting that it not only targets mislocalized or misfolded proteins, but also contributes to homeostasis of resident INM proteins.