Networking in the nucleus: a spotlight on LEM-domain proteins

Abstract

Proteins resident in the inner nuclear membrane and underlying nuclear lamina form a network that regulates nuclear functions. This review highlights a prominent family of nuclear lamina proteins that carries the LAP2-emerin-MAN1-domain (LEM-D). LEM-D proteins share an ability to bind lamins and tether repressive chromatin at the nuclear periphery. The importance of this family is underscored by findings that loss of individual LEM-D proteins causes progressive, tissue-restricted diseases, known as laminopathies. Diverse functions of LEM-D proteins are linked to interactions with unique and overlapping partners including signal transduction effectors, transcription factors and architectural proteins. Recent investigations suggest that LEM-D proteins form hubs within the nuclear lamina that integrate external signals important for tissue homeostasis and maintenance of progenitor cell populations.

Figure 1. The human LEM-D protein family

Shown are the features and subcellular localization of human LEM-D proteins representing each structural group (I, II, III). Most human LEM-D proteins are anchored in the inner nuclear membrane (INM) of the nuclear envelope (NE). Exceptions include LAP2α in the nucleoplasm, the nucleo-cyoplasmic shuttling protein Ankle1 (LEM3), and Ankle2 (LEM4), which localizes at the endoplasmic reticulum in human cells or the NE in C. elegans. LEM-D proteins interact with lamins, forming the nuclear lamina (NL) network. In addition to their LEM domain (LEM-D), members of this family are characterized by the presence or absence of other features including a transmembrane (TM) domain(s), LEM-like domain (LEM-like), MSC (MAN1-Src1-p C-terminal) domain, UHM (U2AF homology motif) domain, GIY-YIG endonuclease domain or ankyrin (ANK) repeats. The arrow indicates nucleo-cytoplasmic shuttling of Ankle1 (LEM3). NPC, nuclear pore complex. ONM, outer nuclear membrane.

Figure 2. LEM-D proteins dynamically influence chromatin attachment to the nuclear envelope

(A). Emerin-lamin and emerin-emerin interactions are regulated by post-translational modifications (PTMs). Multiple PTM sites have been mapped throughout emerin, including serine, threonine and tyrosine (phosphorylation, P in yellow circles) and O-linked β-N-acetylglucosamine modification (O-GlcNAcylation; G in blue hexagons). PTMs are predicted to influence the emerin interactome, with implications for recruitment of BAF and organization of lamina-associated domains (LADs). (B). LEM-D proteins use multiple mechanisms to organize chromatin at the nuclear periphery. LEM-D proteins bind BAF (left). LEM-D proteins associate with HDAC3 to maintain repressive chromatin (middle). The LEM-D protein LAP2β is part of a transcriptional repressor complex that includes HDAC3 and cKrox. cKrox binds GAGA-like DNA elements within Lamina-Associated Sequences (LASs) of LADs, thereby targeting LADs to the nuclear periphery (right). The properties of LEM-D proteins suggest this family contributes to LAD establishment and maintenance.

Figure 3. LEM-D proteins regulate signal transduction

(A). MAN1 directly interacts with Smads causing down-regulation of TGF-β signaling, and emerin directly interacts with β-catenin causing down-regulation of Wnt signaling. Down-regulation of target genes may be due to sequestration of signaling effectors at the nuclear lamina, or increased nuclear export of the effectors. Dashed arrows denote regulation of signaling effector access to their target genes. (B) Emerin has roles in mechanosensory signal transduction. Emerin binding to actin is proposed to influence the nuclear accumulation of MKL1 (left). Mechanical force exerted on LINC complexes leads to increased phosphorylation of tyrosine residues in emerin, which may remodel the emerin-interaction network (right).