AKAP6 orchestrates the nuclear envelope microtubule-organizing center by linking golgi and nucleus via AKAP9

Vergarajaúregui, Silvia; Becker, Robert O.; Steffen, Ulrike; Sharkova, Maria; Esser, Tilman Uli; Petzold, Jana; Billing, Florian; Kapiloff, Michael S.; Schett, G.; Thievessen, Ingo; Engel, Felix B.

doi:10.7554/elife.61669

Cited by 34 publications

(36 citation statements)

References 69 publications

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“…This idea is strongly supported by studies of microtubule organization at the Golgi membranes (Gavilan et al, 2018;Wu et al, 2016) and the apical membranes of polarized epithelial cells, where components of both pathways colocalize and can display some redundancy (Goldspink et al, 2017;Khanal et al, 2016;Noordstra et al, 2016;Toya et al, 2016;Wang et al, 2015). In muscle cells, CAMSAPs are not expressed, and the organization of microtubule minus-ends is driven by the Golgi adaptor AKAP450 and some PCM proteins that are localized to the nuclear envelope and the Golgi (Gimpel et al, 2017;Oddoux et al, 2013;Vergarajauregui et al, 2020). In neurons, minus-ends can be organized by PCM, CAMSAPs, the Golgi membranes and endosomes (Fu et al, 2019;Garbrecht et al, 2021;Liang et al, 2020;Magescas et al, 2021;Pongrakhananon et al, 2018;Yau et al, 2014), though the cross-talk between different pathways is insufficiently understood.…”

Section: Discussionmentioning

confidence: 95%

Self-assembly of pericentriolar material in interphase cells lacking centrioles

Chen

Iwanski

et al. 2021

Preprint

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The major microtubule-organizing center (MTOC) in animal cells, the centrosome, comprises a pair of centrioles surrounded by pericentriolar material (PCM), which nucleates and anchors microtubules. Centrosome assembly depends on the interactions of PCM with centrioles, PCM self-association and dynein-mediated transport. Here, we show that if centrioles are lost due to PLK4 depletion or inhibition, PCM still forms a single centrally located MTOC when non-centrosomal microtubule minus end organization pathways are disabled. Acentriolar MTOC assembly depends on dynein-driven coalescence of PCM clusters with attached microtubule minus ends and requires γ-tubulin, pericentrin, CDK5RAP2 and ninein, but not NEDD1, CEP152 or CEP192. PCM self-assembly is inhibited by AKAP450-dependent PCM recruitment to the Golgi and by CAMSAP2-mediated microtubule minus end stabilization. However, if CAMSAP2 is linked to a minus-end-directed motor, a single MTOC containing PCM components can still form, and its organization depends on the presence of pericentrin. Our results reveal that the formation of a single central MTOC in interphase mammalian cells is not strictly centriole dependent but can be driven by self-organization of PCM and microtubule minus ends.

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Section: Discussionmentioning

confidence: 95%

Self-assembly of pericentriolar material in interphase cells lacking centrioles

Chen

Iwanski

et al. 2021

Preprint

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“…sarcomeres, mitochondria, and t-tubules, invaginations of the muscle cell membrane) as well as efficient microtubule-based intracellular transport [38]. Notable, it has recently been demonstrated that the nuclear MTOC is required for cardiomyocyte hypertrophy [19]. In the future it will be important to determine whether Pcnt S has any specific role at the nuclear MTOC and to establish systems in which the nuclear envelope MTOC can be modulated and cellular organization and function can be assessed.…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing of pericentrin contributes to cell cycle control in cardiomyocytes

Steinfeldt

Becker

Vergarajaúregui

et al. 2021

Preprint

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Induction of cardiomyocyte proliferation is a promising option to regenerate the heart. Thus, it is important to elucidate mechanisms that contribute to the cell cycle arrest of mammalian cardiomyocytes. Here, we assessed the contribution of the pericentrin (Pcnt) S isoform to the cell cycle arrest in postnatal cardiomyocytes. Immunofluorescence staining of Pcnt isoforms combined with siRNA-mediated depletion indicates that Pcnt S preferentially localizes to the nuclear envelope, while the Pcnt B isoform is enriched at centrosomes. This is further supported by the localization of ectopically expressed FLAG-tagged Pcnt S and Pcnt B in postnatal cardiomyocytes. Analysis of centriole configuration upon Pcnt depletion revealed that Pcnt B but not Pcnt S is required for centriole cohesion. Importantly, ectopic expression of Pcnt S induced centriole splitting in a heterologous system, ARPE-19 cells, and was sufficient to impair DNA synthesis in C2C12 myoblasts. Moreover, Pcnt S depletion enhanced serum-induced cell cycle re-entry in postnatal cardiomyocytes. Analysis of mitosis, binucleation rate, and cell number suggests that Pcnt S depletion promotes progression of postnatal cardiomyocytes through the cell cycle resulting in cell division. Collectively, our data indicate that alternative splicing of Pcnt contributes to the establishment of cardiomyocyte cell cycle arrest shortly after birth.

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“…The current body of research about the organization and importance of the LINC complex in adult striated muscle cells comes from recent studies in cardiomyocytes ( Heffler et al, 2020 ); however, cardiomyocytes are either mono- or bi-nucleated, with the nucleus located in the center of the cell ( Janin and Gache, 2018 ). In cardiac cells, microtubules interact with the nucleus via AKAP6 and AKAP9 ( Vergarajauregui et al, 2020 ); AKAP9 serves an additional function in skeletal muscle cells, where it is required for microtubule-mediated nuclear migration ( Gimpel et al, 2017 ). Interestingly, another microtubule-organizing protein, pericentriolar material 1 (PCM1), is enriched on myonuclei in adult muscle ( Winje et al, 2018 ).…”

Section: Complexes Involved In Nuclear Mechanotransductionmentioning

confidence: 99%

“…Microtubules play an important role in mechanotransduction in cardiac cells ( Kerr et al, 2015 ; Vergarajauregui et al, 2020 ), where they form a cage-like structure around the nucleus. Similar cage-like structures are observed in skeletal muscle cells ( Becker et al, 2020 ; Earle et al, 2020 ), although the significance of these microtubule-myonuclear interactions on nuclear morphology and mechanotransduction requires additional investigation.…”

Section: Complexes Involved In Nuclear Mechanotransductionmentioning

confidence: 99%

LINCing Nuclear Mechanobiology With Skeletal Muscle Mass and Function

Ingen

Kirby

2021

Front. Cell Dev. Biol.

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Skeletal muscle demonstrates a high degree of adaptability in response to changes in mechanical input. The phenotypic transformation in response to mechanical cues includes changes in muscle mass and force generating capabilities, yet the molecular pathways that govern skeletal muscle adaptation are still incompletely understood. While there is strong evidence that mechanotransduction pathways that stimulate protein synthesis play a key role in regulation of muscle mass, there are likely additional mechano-sensitive mechanisms important for controlling functional muscle adaptation. There is emerging evidence that the cell nucleus can directly respond to mechanical signals (i.e., nuclear mechanotransduction), providing a potential additional level of cellular regulation for controlling skeletal muscle mass. The importance of nuclear mechanotransduction in cellular function is evident by the various genetic diseases that arise from mutations in proteins crucial to the transmission of force between the cytoskeleton and the nucleus. Intriguingly, these diseases preferentially affect cardiac and skeletal muscle, suggesting that nuclear mechanotransduction is critically important for striated muscle homeostasis. Here we discuss our current understanding for how the nucleus acts as a mechanosensor, describe the main cytoskeletal and nuclear proteins involved in the process, and propose how similar mechanoresponsive mechanisms could occur in the unique cellular environment of a myofiber. In addition, we examine how nuclear mechanotransduction fits into our current framework for how mechanical stimuli regulates skeletal muscle mass.

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AKAP6 orchestrates the nuclear envelope microtubule-organizing center by linking golgi and nucleus via AKAP9

Cited by 34 publications

References 69 publications

Self-assembly of pericentriolar material in interphase cells lacking centrioles

Self-assembly of pericentriolar material in interphase cells lacking centrioles

Alternative splicing of pericentrin contributes to cell cycle control in cardiomyocytes

LINCing Nuclear Mechanobiology With Skeletal Muscle Mass and Function

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