Outfits for different occasions: tissue-specific roles of Nuclear Envelope proteins

Abstract

The Nuclear Envelope (NE) contains over 100 different proteins that associate with nuclear components such as chromatin, the lamina and the transcription machinery. Mutations in genes encoding NE proteins have been shown to result in tissue-specific defects and disease, suggesting cell-type specific differences in NE composition and function. Consistent with these observations, recent studies have revealed unexpected functions for numerous NE associated proteins during cell differentiation and development. Here we review the latest insights into the roles played by the NE in cell differentiation, development, disease and aging, focusing primarily on inner nuclear membrane (INM) proteins and nuclear pore components.

Figure 1

(A) LEM2 is a negative regulator of ERK signaling during muscle differentiation. Although the mechanism by which ERK1/2 is inhibited is unclear, one possibility could be through the sequestration of ERK1/2 to the nuclear periphery. Emerin has been shown to play a role in two different signaling cascades. First, it negatively regulates Wnt signaling by preventing accumulation of β-catenin in the nucleus, presumably by stimulating export of β-catenin. Second, emerin negatively regulates ERK signaling through unclear mechanisms. MAN1 negatively regulates TGF-β signaling by sequestering R-Smads away from gene targets. (B) During myogenesis, NET39 acts as a repressor of the mTOR-IGF-II signaling pathway. NET39 blocks IGF-II transcription by inhibiting mTOR activity at the NE. NET37, an INM protein with glycosidase activity promotes myogenesis by activating AKT signaling through the maturation and secretion of IGF-II in the PNS/ER.

Figure 2

(A) NUP155 regulates the export of Hsp70 mRNA and import of Hsp70 protein in cardiac muscle, a function NUP155 loses in atrial fibrillation. In cardiomyocytes, NUP155 mediates localization and activity of HDAC4. Addition of NUP210 to NPCs induces activation of genes critical for myogenesis and the differentiation of ES cells into NP cells. In Drosophila, several dynamic NPC components shuttle off the pore to regulate the expression of developmental genes inside the nucleoplasm. (B) Lack of a replacement mechanism of NPCs in post-mitotic cells results in deterioration of NPCs over time and progressive loss of cell compartmentalization.