The C. elegans Hook Protein, ZYG-12, Mediates the Essential Attachment between the Centrosome and Nucleus

Malone, Christian J.; Misner, Lisa; Bot, Nathalie Le; Tsai, Ming Ying; Campbell, Jay M.; Ahringer, Julie; White, John

doi:10.1016/s0092-8674(03)00985-1

Cited by 386 publications

(622 citation statements)

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“…UNC-84 is a novel protein with a predicted transmembrane domain near the center of the protein and a conserved domain at its C terminus. SUN domains are conserved across all eukaryotes and include S. pombe Sad1p, C. elegans UNC-84 and SUN-1, four human Sun proteins, and even a homologue in the most basal eukaryote Giardia (GenBank EAA41593) (Hagan and Yanmagida, 1995;Malone et al, 1999Malone et al, , 2003Hodzic et al, 2004;Padmakumar et al, 2005;Starr and Fischer, 2005). UNC-84 localizes to the nuclear envelope in nearly all somatic cells from the 24-cell stage on in development .…”

Section: Introductionmentioning

confidence: 99%

“…Although UNC-83 is essential for nuclear migration in many developmental events, its molecular mechanism and interacting partners remain unknown. UNC-84 is a novel protein with a (Hagan and Yanmagida, 1995;Malone et al, 1999Malone et al, , 2003Hodzic et al, 2004;Padmakumar et al, 2005;Starr and Fischer, 2005). UNC-84 localizes to the nuclear envelope in nearly all somatic cells from the 24-cell stage on in development .…”

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UNC-83 Is a KASH Protein Required for Nuclear Migration and Is Recruited to the Outer Nuclear Membrane by a Physical Interaction with the SUN Protein UNC-84

McGee

Rillo

Anderson

et al. 2006

MBoC

128

180

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UNC-84 is required to localize UNC-83 to the nuclear envelope where it functions during nuclear migration. A KASH domain in UNC-83 was identified. KASH domains are conserved in the nuclear envelope proteins Syne/nesprins, Klarsicht, MSP-300, and ANC-1. Caenorhabditis elegans UNC-83 was shown to localize to the outer nuclear membrane and UNC-84 to the inner nuclear membrane in transfected mammalian cells, suggesting the KASH and SUN protein targeting mechanisms are conserved. Deletion of the KASH domain of UNC-83 blocked nuclear migration and localization to the C. elegans nuclear envelope. Some point mutations in the UNC-83 KASH domain disrupted nuclear migration, even if they localized normally. At least two separable portions of the C-terminal half of UNC-84 were found to interact with the UNC-83 KASH domain in a membrane-bound, split-ubiquitin yeast two-hybrid system. However, the SUN domain was essential for UNC-84 function and UNC-83 localization in vivo. These data support the model that KASH and SUN proteins bridge the nuclear envelope, connecting the nuclear lamina to cytoskeletal components. This mechanism seems conserved across eukaryotes and is the first proposed mechanism to target proteins specifically to the outer nuclear membrane. INTRODUCTIONA variety of cellular and developmental processes, including fertilization, cell division, cell migration, and establishment of polarity, depend on positioning the nucleus to a specific location within the cell. For example, in budding yeast the nucleus must migrate to the bud neck before the onset of mitosis. Also, nuclei actively follow the leading edge of migratory cells, such as those in the developing cerebral cortex. Nuclear migration defects in these two examples lead to the missegregation of chromosomes or the neurological disease lissencephaly, respectively (reviewed in Morris, 2000). The role of microtubules and associated dynein and kinesin motors in nuclear migration are well established (reviewed in Reinsch and Gonczy, 1998). Although less established, actin also plays an important role in many nuclear positioning events (reviewed in Starr and Han, 2003). Recently, a definitive role for actin networks has been described in nuclear migration during NIH 3T3 cell polarization (Gomes et al., 2005). It remains relatively unknown how the nucleus connects to the cytoplasmic cytoskeleton during nuclear migration. Furthermore, it is not clear how the forces involved in nuclear positioning are transferred across both membranes of the nuclear envelope from the cytoskeleton to the nuclear matrix.We have previously proposed that two C. elegans proteins, UNC-84 and UNC-83, function to control nuclear migration by bridging the nuclear envelope, connecting the cytoskeleton with the nuclear matrix (Starr et al., 2001;Lee et al., 2002;Starr and Han, 2003). Mutations in unc-83 or unc-84 disrupt nuclear migration in at least three cell types: embryonic hypodermal hyp7 precursors, larval hypodermal P-cells, and embryonic intestinal primordial cells (Horvitz and Sulst...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

UNC-83 Is a KASH Protein Required for Nuclear Migration and Is Recruited to the Outer Nuclear Membrane by a Physical Interaction with the SUN Protein UNC-84

McGee

Rillo

Anderson

et al. 2006

MBoC

128

180

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“…In higher eukaryotes, the link between the nuclear envelope and the centrosome is essential 220 for development [63] and is robust enough to withstand cell lysis and nuclear isolation [64]. 221…”

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confidence: 99%

“…First discovered in C. elegans, proteins with these domains are 228 found across eukaryotes and localise to the nuclear envelope and centrosomes [63,[66][67][68]. anchors the centrosome to the nuclear envelope during embryogenesis [63]. ZYG-12 is not 233 found in mammalian cells; however several proteins fulfill the role of nucleus-centrosome 234 linkers including the nuclear membrane protein emerin [71], and the multi-isoform KASH 235 protein Nesprin 2 [66].…”

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Common themes in centriole and centrosome movements

Vaughan

Dawe

2011

Trends in Cell Biology

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LINC Complexes and Their Role in Human Disease

Calvi

Burke

2015

Encyclopedia of Life Sciences

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In most metazoan cell types, the nucleus occupies a clearly defined region of the cytoplasm. For instance in epithelial cells, it is commonly positioned close to the basal membrane, whereas in skeletal muscle fibres, the majority of nuclei are uniformly distributed adjacent to the plasma membrane. A few muscle cell nuclei, however, cluster beneath the postsynaptic membrane. In certain cell types, the nucleus may be repositioned according to cell cycle phase or cell activity. Each of these situations requires that nuclei be physically coupled to the cytoskeleton. This is accomplished in large part by LINC (linker of the nucleoskeleton and cytoskeleton) complexes. These structures consist of inner nuclear membrane SUN (Sad1p‐UNC‐84)‐domain proteins that function as transluminal tethers for outer nuclear membrane KASH ‐domain proteins. Together, SUN–KASH pairs function as links in a molecular chain that couples cytoskeletal elements, including motor proteins, to nuclear components. In addition to having obligate roles in nuclear positioning and chromatin organisation, LINC complexes may also function in mechanotransduction. The fact that a number of human diseases have been associated with LINC complex defects indicates that in many cell types these represent essential structures at the interface between the nucleus and cytoplasm. Key Concepts The nuclear envelope forms the interface between the nucleus and cytoplasm. Its most prominent features are the inner and outer nuclear membranes (INM and ONM) separated by a narrow (∼50 nm) gap, the perinuclear space (PNS). SUN domain proteins of the INM function as transluminal tethers for KASH domain proteins in the ONM. The nucleoplasmic domain of SUN proteins provides binding sites for both chromatin proteins and components of the nuclear lamina. KASH domain proteins represent attachment sites at the nuclear envelope for a variety of cytoskeletal elements, including motor proteins. SUN–KASH pairs, which span both nuclear membranes, are known as LINC (linker of the nucleoskeleton and cytoskeleton) complexes and mechanically couple nuclear structures to the cytoskeleton. LINC complexes have essential roles in nuclear migration and positioning in multiple cell types. During meiosis, LINC complexes have an essential role in telomere‐led chromosome movement, a process that facilitates homologous chromosome pairing and synapsis. LINC complexes are thought to mediate the transmission of mechanical signals to the nucleus: mechanotransduction.

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The C. elegans Hook Protein, ZYG-12, Mediates the Essential Attachment between the Centrosome and Nucleus

Cited by 386 publications

References 50 publications

UNC-83 Is a KASH Protein Required for Nuclear Migration and Is Recruited to the Outer Nuclear Membrane by a Physical Interaction with the SUN Protein UNC-84

UNC-83 Is a KASH Protein Required for Nuclear Migration and Is Recruited to the Outer Nuclear Membrane by a Physical Interaction with the SUN Protein UNC-84

Common themes in centriole and centrosome movements

LINC Complexes and Their Role in Human Disease

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