The Diverse Cellular Functions of Inner Nuclear Membrane Proteins

Abstract

The nuclear compartment is delimited by a specialized expanded sheet of the endoplasmic reticulum (ER) known as the nuclear envelope (NE). Compared to the outer nuclear membrane and the contiguous peripheral ER, the inner nuclear membrane (INM) houses a unique set of transmembrane proteins that serve a staggering range of functions. Many of these functions reflect the exceptional position of INM proteins at the membrane-chromatin interface. Recent research revealed that numerous INM proteins perform crucial roles in chromatin organization, regulation of gene expression, genome stability, and mediation of signaling pathways into the nucleus. Other INM proteins establish mechanical links between chromatin and the cytoskeleton, help NE remodeling, or contribute to the surveillance of NE integrity and homeostasis. As INM proteins continue to gain prominence, we review these advancements and give an overview on the functional versatility of the INM proteome.

Figure 1.

Schematic representation of well-characterized inner nuclear membrane (INM) proteins indicating their membrane topology, domain organization, and known interaction partners. INM proteins bind chromatin, chromatin-associated factors, and nuclear lamins as indicated. Certain INM proteins like lamin B receptor (LBR) and LAP2-Emerin-Man1 (LEM)-domain proteins bind transcription factors and thereby modulate gene expression. Additionally, some INM proteins bind to each other while others, like LBR, self-interact, altogether creating a complex network of interactions. At the INM, Sad1p, Unc-84 (SUN) domain proteins form trimers via their coiled-coil domains and interact with three KASH peptides of outer nuclear membrane (ONM)-resident Nesprins to form the LINC (linker of nucleoskeleton and cytoskeleton) complex.

Figure 2.

The diverse functions of inner nuclear membrane (INM) proteins. (A) Many INM proteins tether chromatin to the nuclear envelope (NE) and facilitate repression of genomic elements. Some INM proteins assist processes such as splicing, DNA replication, or the DNA damage response. (B) Members of the LINC (linker of nucleoskeleton and cytoskeleton) complex have mechanical and structural roles, interlinking the nucleoskeleton and cytoskeleton and thereby acting as force transmission devices across the NE. LINC complexes perform a wide range of functions, including nuclear anchorage and migration, chromosome movements, and the maintenance of NE membrane spacing. Other INM proteins (e.g., emerin and SAMP1) may functionally collaborate with LINC complexes in mechanotransduction. (C) INM proteins interact with transcription factors to regulate gene expression, thereby contributing to diverse signaling pathways. (D) Certain INM proteins possess enzymatic functions. Lamin B receptors (LBRs) exhibit C14 sterol reductase activity that is used in cholesterol synthesis. Others, like LAP1 and LEM2, directly or indirectly regulate the activities of partner proteins such as Torsins and the ESCRT-III complex, respectively.