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Actin Cytoskeleton

The nuclear envelope and the actin cytoskeleton

Nesprins are novel components of the nuclear envelope
The nuclear envelope (NE) separates the cytoplasmic and nuclear compartment of eukaryotic cells. It is formed by an inner and outer nuclear membrane (INM, ONM), nuclear pore complexes which allow trafficking in and out of the nucleus and the underlying lamina. The ONM is continous with the endoplasmic reticulum, to which it is functionally related, whereas the INM is characterized by a specific set of proteins which associate with the nuclear lamina as well as with chromatin.
In a screen for novel actin binding proteins containing an -actinin-like ABD we have identified Nesprin-1/Enaptin and Nesprin-2/NUANCE (Zhen et al., 2002; Padmakumar et al., 2004). Nesprin-1/Enaptin and Nesprin-2/NUANCE are structurally related large proteins with molecular weights of 796 and 1014 kDa, respectively, which are encoded by separate genes (SYNE1, SYNE2). The human Nesprin-1 gene is located on chromosome 6q25, the human Nesprin-2 gene is on chromosome 14q23.3.
Nesprins are type II membrane proteins composed of an N-terminal alpha-actinin-like actin-binding domain, a long rod domain which harbors spectrin repeats and a unique transmembrane domain at their C-terminus which anchors them in the nuclear membrane. This structure suggests that Nesprins have the potential to organize cellular interactions and to orchestrate the interaction between the nucleus and the cytoskeleton. Nesprin-1 and Nesprin-2 show a tissue specific expression pattern. Nesprin-1 is highly expressed in brain, skeletal muscle, heart, stomach, pancreas and kidney, Nesprin-2 is strongly expressed in stomach, kidney and lymphoid tissue.

Figure 1: Nesprin-2 is present at the nuclear envelope. COS7 cells are stained with a Nesprin-2 specific monoclonal antibody.

Lüke, Y., Zaim, H., Karakesisoglou, I., Jaeger, V. M., Sellin, L., Lu, W., Schneider, M., Padmakumar, V. C., Beijer, A., Neumann, S., Munck, M., Gloy, J., Walz, G., Noegel, A. A. (2008). Nesprin-2 Giant / NUANCE maintains nuclear envelope architecture and composition in skin. J. Cell Sci. 121, 1887-1898.

Zhen, Y.-Y., Libotte, T., Munck, M., Noegel, A. A., Korenbaum, E. (2002). NUANCE, a giant protein connecting nucleus and actin cytoskeleton. J. Cell Sci. 115, 3207-3222.

Padmakumar, V. C., Abraham, S., Braune, S., Noegel, A. A., Tunggal, B., Karakesisoglou, I., Korenbaum, E. (2004). Enaptin, a giant actin-binding protein, is an element of the nuclear membrane and the actin cytoskeleton. Exp. Cell Res. 295, 330-339.

Nesprin interactions at the nuclear envelope
Nesprins are type II transmembrane proteins and are anchored with their transmembrane domain in the nuclear membrane. The transmembrane domain is followed by a short C-terminal domain of about 30 amino acids that resides in the perinuclear space. This domain is highly conserved. It is present in Nesprin-1 and Nesprin-2 and through this region Nesprins associate with SUN-proteins in the perinuclear space and are retained in the nuclear membrane (Padmakumar et al., 2005). Nesprins also interact with components of the inner aspect of the NE where they bind to lamin A/C and emerin. The binding sites have been mapped near the C-terminus of Nesprin-1 and Nesprin-2 (Libotte et al., 2005). The disruption of these interactions may have severe consequences, and indeed mutations in the Nesprin-1 and Nesprin-2 genes have recently been identified that are associated with an autosomal recessive cerebellar ataxia and with Emery-Dreifuss muscular dystrophy.

Figure 2: Model illustrating the interactions of Sun1 with Nesprins at the nuclear envelope. Nesprins are held in the nuclear envelope through interactions with the C-terminal domain of Sun1. With their N-terminal domains they can undergo interactions with components of the nucleoplasm for a Nesprin anchored in the inner nuclear membrane (INM) or of the cytoplasm for a Nesprin anchored in the outer nuclear membrane (ONM) (taken from Padmakumar et al., 2005).

Libotte, T., Zaim, H., Abraham, S., Padmakumar, V. C. Schneider, M., Lu, W., Munck, M., Hutchison, C., Wehnert, M., Fahrenkrog, B., Sauder, U., Aebi, U., *Noegel, A. A., Karakesisoglou, I. (2005). Lamin A/C dependent localization of Nesprin-2, a giant scaffolder at the nuclear envelope. Mol. Biol. Cell 16, 3411-3424.

Padmakumar, V.C., Libotte, T., Lu, W., Zaim, H., Abraham, S., Noegel, A. A., Gotzmann, J., Foisner, R., Karakesisoglou, I. (2005). Sun1, an inner nuclear membrane protein, mediates the anchorage of Nesprin-2 to the nuclear envelope. J. Cell Sci. 118, 3419-3430.

The nuclear envelope in Dictyostelium discoideum
In higher eukaryotes the nuclear envelope consists of the outer and inner nuclear membrane, the nuclear pore complexes and an underlying network of filaments, the lamina which is composed of lamins and lamin-binding proteins. As pointed out by recent discoveries, lamins are not only structural proteins but are also major players in essential nuclear functions and have both scaffolding as well as anchoring roles for chromatin, the transcription machinery and transcription factors.
Lower eukaryotes and plants do not harbour lamins. It is assumed that they have distinct nuclear structural proteins and binding partners that fulfill similar functions as the nuclear lamins and lamin-associated proteins. Different strategies may therefore have evolved to perform similar tasks. Although D. discoideum does not have lamins it harbors a Nesprin homologue, which is called interaptin (Rivero et al., 1998), and Sun-1, a Sun domain protein (Xiong et al., 2008). Sun-1 of D. discoideum is a key player in spacing of the nuclear envelope lumen. It interacts with chromatin to establish centrosome-nucleus juxtaposition that ensures concerted division of both organelles. Abrogation of chromatin binding of Sun-1 induces centrosome amplification and aneuploidy.

Figure 3: Sun-1 in D. discoideum (red, Sun-1; blue, DAPI)

Rivero, F., Kuspa, A., Brokamp, R., Matzner, M., Noegel, A. A. (1998). Interaptin, an actin-binding protein of the alpha-actinin superfamily in Dictyostelium discoideum, is developmentally and cAMP-regulated and associates with intracellular membrane compartments. J. Cell Biol. 142, 735-750.

Xiong, H., Rivero, F., Euteneuer, U., Mondal, S., Mana-Capelli, S., Larochelle, D., Vogel, A., Gassen, B., Noegel, A. A. (2008). Dictyostelium Sun-1 connects the centrosome to chromatin and ensures genome stability. Traffic 9, 708-724

March 14, 2012
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