LINC complexes and nuclear positioning

Lee, Yin Loon; Burke, Brian

doi:10.1016/j.semcdb.2017.11.008

Cited by 87 publications

(79 citation statements)

References 115 publications

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“…8 Nesprin-2 can also indirectly bind actin through fascin 9 and FHOD1 10 , possibly reinforcing its mechanical link to actin. Nesprin-1 and nesprin-2 bind microtubules through kinesin-1 and dynein 11 and plectin can link another nesprin, nesprin-3, to the intermediate filament vimentin. 12 Nesprins are implicated in nuclear movement and positioning in fibroblasts and muscle cells 13 , outer hair cells 14 , and during retinal and neuronal cell development.…”

Section: Introductionmentioning

confidence: 99%

“…12 Nesprins are implicated in nuclear movement and positioning in fibroblasts and muscle cells 13 , outer hair cells 14 , and during retinal and neuronal cell development. 11,15 In particular, nesprin-2 giant determines nuclear re-centering after displacement due to centripetal forces in NIH 3T3 fibroblasts (that do not express nesprin-1 giant) 16 . Nesprin-2 also enables migration through 5 um constriction and restrictive collagen gels, in concert with non-muscle myosin IIb, an actin motor protein.…”

Section: Introductionmentioning

confidence: 99%

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Nesprin-2 accumulates at the front of the nucleus during confined cell migration

Davidson

Battistella

Déjardin

et al. 2019

Preprint

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The mechanisms by which cells exert forces on their nuclei to migrate through openings smaller than the nuclear diameter remain unclear. In microfluidic devices, the hourglass shape of the nucleus and its strain patterns as it translocates through narrow constrictions suggest pulling forces. We use CRISPR/Cas9 to label nesprin-2 giant, a protein that links the cytoskeleton to the interior of the nucleus. We demonstrate that nesprin-2 giant accumulates at the front of the nucleus during nuclear deformation through narrow constrictions, independently of the nuclear lamina. We find that nesprins are more mobile than lamin A/C, and hypothesize that nesprin accumulation at the front is a consequence of forward pulling by the cytoskeleton. Using artificial constructs, we show indeed that the actin-binding domain of nesprin-2 is necessary and sufficient to generate this accumulation, and that microtubules are not involved. Actin filaments are organized in a barrel structure around the moving nucleus in the direction of movement. This and estimates of nesprin elongation suggest that actin pulling forces on nesprins are distributed around the deformed nucleus towards the front.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nesprin-2 accumulates at the front of the nucleus during confined cell migration

Davidson

Battistella

Déjardin

et al. 2019

Preprint

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“…Kinesin-1 (Metzger et al, 2012), and Dynein for myonuclear positioning/nuclear morphology, but these proteins are not required for fat body MTOC organization or nuclear positioning. In addition, Nesprins can anchor MTs through associations with MT motors in other systems (Lee and Burke, 2018), but the role described here for Msp300 is distinct from those mechanisms because in the fat body Msp300 is a structural platform for assembly of the ncMTOC at the nuclear surface, seemingly independent of Kinesin-1 or Dynein motors. Morever, depletion of Nesprin-1 or SUN1/2 in mammalian muscle cells shifts the perinuclear MTOC to ectopic MTOCs associated with perinuclear Golgi complexes (Gimpel et al, 2017), an MTOC switch similar but distinctily different from shot depletion in fat body cells.…”

Section: A Nesprin-shot Complex Anchors the Mtoc At The Nuclear Surfacementioning

confidence: 85%

A perinuclear microtubule-organizing center controls nuclear positioning and basement membrane secretion

Zheng¹,

Buchwalter²,

Zheng³

et al. 2019

Preprint

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Non-centrosomal microtubule-organizing centers (ncMTOCs) have a variety of roles presumed to serve the diverse functions of the range of cell types in which they are found. ncMTOCs are diverse in their composition, subcellular localization, and function. Here we report a novel perinuclear MTOC in Drosophila fat body cells that is anchored by Msp300/Nesprin at the cytoplasmic surface of the nucleus. Msp300 recruits the MT minus-end protein Patronin/CAMSAP, which functions redundantly with Ninein to further recruit the MT polymerase Msps/XMAP215 to assemble noncentrosomal MTs and does so independently of the widespread MT nucleation factor g-tubulin.Functionally, the fat body ncMTOC and the radial MT arrays it organizes is essential for nuclear positioning and for secretion of basement membrane components via retrograde dynein-dependent endosomal trafficking that restricts plasma membrane growth. Together, this study identifies a perinuclear ncMTOC with unique architecture and MT regulation properties that serves vital functions. Highlights• A novel perinuclear MTOC in differentiated fat body cells • The predominant nucleator, g-tubulin, is not required at the fat body ncMTOC • Msp300/Nesprin organizes the ncMTOC at the nuclear surface by recruiting Patronin/CAMSAP and the spectraplakin Shot • Patronin cooperates with Ninein to control MT assembly at the fat body ncMTOC by recruiting Msps • Msps, a MT polymerase, is essential for radial MT elongation from the fat body ncMTOC • Patronin and Msps associate • The ncMTOC and radial MTs, but not actin, control nuclear positioning in the fat body • The fat body MTOC controls retrograde endocytic trafficking to regulate plasma membrane growth and secretion of basement membrane proteins Here we report the discovery of an ncMTOC that is assembled on the surface of nuclei in Drosophila larval fat body cells, a differentiated cell type that has critical secretory functions and serves the metabolic needs of the organism. Assembly of this perinuclear ncMTOC requires the Msp300/Nesprin (nuclear envelope spectrin repeat protein) as a primary organizer/anchor. Msp300 recruits Patronin, which functions redundantly with Ninein for MT assembly at the ncMTOC. Patronin and Ninein cooperate to recruit Msps, which is essential for the elongation of MTs from the fat body ncMTOC. Recruitment of Msps and MT assembly at the ncMTOC are independent of g-tubulin. Functionally, this ncMTOC is necessary for: 1) the regulation of nuclear positioning, 2) controlling plasma membrane growth by facilitating dynein/Rab5-mediated retrograde endosomal trafficking of excess plasma membrane, and 3) the secretion of collagen IV and other basement membrane (BM) proteins. Together, this study identifies a unique perinuclear ncMTOC with novel MT assembly mechanisms that controls physiological roles of fat body cells by supporting nuclear positioning and vital secretory functions of fat body cells.

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“…The LINC complex is essential for nuclear shape and positioning in almost all eukaryotic cells, and fulfils a number of specialised roles, such as in hearing and meiotic cell division (Lee and Burke, 2018;Meinke and Schirmer, 2015;Starr and Fridolfsson, 2010). As a mechanical transducer, the structure-function relationship underlies the highly diverse cellular roles of the LINC complex.…”

Section: Discussionmentioning

confidence: 99%

“…This is achieved by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which traverses the nuclear envelope and binds to cytoskeletal and nuclear structures to mediate force transduction between these partitioned components (Starr and Fridolfsson, 2010) ( Figure 1a). In this capacity, the LINC complex is essential for cellular life, performing critical functions in nuclear structure, shape and positioning, in addition to tissue-specific functions including sound perception in the inner ear and chromosome movements during meiosis (Lee and Burke, 2018;Meinke and Schirmer, 2015;Starr and Fridolfsson, 2010). Further, mutations of the LINC complex and its interacting partners are associated with human laminopathies, including Hutchison-Gilford progeria syndrome and Emery-Dreifuss muscular dystrophy (Meinke et al, 2011;Mejat and Misteli, 2010).…”

Section: Introductionmentioning

confidence: 99%

A molecular mechanism for LINC complex branching by structurally diverse SUN-KASH 6:6 assemblies

Gurusaran

Davies

2020

Preprint

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The LINC complex mechanically couples cytoskeletal and nuclear components across the nuclear envelope to fulfil a myriad of cellular functions, including nuclear shape and positioning, hearing and meiotic chromosome movements. The canonical model of the LINC complex is of individual linear nucleocytoskeletal linkages provided by 3:3 interactions between SUN and KASH proteins. Here, we provide crystallographic and biophysical evidence that SUN-KASH is a constitutive 6:6 complex in which two SUN trimers interact back-to-back. A common SUN-KASH topology is achieved through structurally diverse 6:6 interaction mechanisms by distinct KASH proteins, including zinc-coordination by Nesprin-4. The SUN-KASH 6:6 complex is incompatible with the current model of a linear LINC complex and instead suggests the formation of a branched LINC complex network. In this model, SUN-KASH 6:6 complexes act as nodes for force distribution and integration between adjacent SUN and KASH molecules, enabling the coordinated transduction of large forces across the nuclear envelope. KeywordsLINC complex, nuclear envelope, SUN1, Nesprin-4, KASH5, Nesprin-1, X-ray crystallography, smallangle X-ray scattering, biophysics SUN proteins then traverse the approximately 50 nm peri-nuclear space and cross the inner nuclear membrane, enabling their N-termini to bind to nuclear contents, including reported interactions with the nuclear lamina (Crisp et al., 2006; Haque et al., 2006; Haque et al., 2010), chromatin (Chi et al., 2007) and the telomeric ends of meiotic chromosomes (Shibuya et al., 2014). Similarly, KASH domain proteins cross the outer nuclear membrane and have large cytoplasmic extensions to enable their Ntermini to bind to the cytoskeleton (Spindler et al., 2019; Starr and Fridolfsson, 2010). Thus, the LINC complex axis is established by a peri-nuclear SUN-KASH core interaction and mechanically couples the cytoskeleton and nuclear contents (Figure 1a). In mammals, there are five SUN proteins, of which SUN1 and SUN2 are widely expressed and perform partially redundant functions (Lei et al., 2009; Zhang et al., 2009). There are similarly multiple KASH proteins, four of which are Nesprins (Nuclear Envelope Spectrin Repeat proteins). Nesprin-1 and Nesprin-2 are widely expressed, perform overlapping functions and contain large cytoplasmic spectrin-repeat domains with N-termini that bind to actin (Banerjee et al., 2014; Starr and Fridolfsson, 2010). Nesprin-3 shares a similar KASH domain but its cytoplasmic region binds to plectin, mediating interactions with intermediate filaments (Ketema and Sonnenberg, 2011). The two most divergent KASH proteins, Nesprin-4 and KASH5, exhibit substantial sequence diversity within their KASH domains (Figure 1b). Nesprin-4 functions in the outer hair cells of the inner ear and is essential for hearing (Horn et al., 2013a). Its N-terminus interacts with kinesin, which mediates microtubule binding and plus-end directed movements that achieve the basal positioning of nuclei (Horn et al., 2013a; Roux et al., 2009). KA...

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LINC complexes and nuclear positioning

Cited by 87 publications

References 115 publications

Nesprin-2 accumulates at the front of the nucleus during confined cell migration

Nesprin-2 accumulates at the front of the nucleus during confined cell migration

A perinuclear microtubule-organizing center controls nuclear positioning and basement membrane secretion

A molecular mechanism for LINC complex branching by structurally diverse SUN-KASH 6:6 assemblies

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