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Plectin isoform 1-dependent nuclear docking of desmin networks affects myonuclear architecture and expression of mechanotransducers.

Staszewska I, Fischer I, Wiche G - Hum. Mol. Genet. (2015)

Bottom Line: We show that P1-mediated targeting of desmin IFs to myonuclei is essential for maintenance of their typically spheroidal architecture as well as their proper positioning and movement along the myofiber.Mechanistically, P1 is shown to specifically interact with the myonuclear membrane-associated (BAR domain-containing) protein endophilin B.Our results open a new perspective on cytoskeleton-nuclear crosstalk via specific cytolinker proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.

No MeSH data available.


Related in: MedlinePlus

Schematic model of cell organization and nuclear morphology typical of wild-type and P1-KO myofibers. (A) Each one of four major plectin isoforms expressed in myofibers is targeted to a different cellular compartment: P1 to the nuclear/ER membrane system, P1b to mitochondria, P1d to Z-disks and P1f to the sarcolemma. All of these isoforms recruit desmin IFs via their C-terminal IF-binding domain to these respective sites, thereby controlling IF network architecture and reinforcing the structural integrity of myofibers. P1 is predominantly localized at tail-like structures longitudinally extending from the nuclear equator. Desmin IFs recruited by P1 form a cage-like structure around nuclei, which holds nuclei under isometric tension, enabling their immediate response to mechanical stimuli. Ellipsoidally shaped, elongated nuclei are spatially distributed all along the myofiber. P1 targeting and nuclear docking occurs via nucleus-associated proteins, such as nesprin-3 and endophilin B. (B) In P1-deficient myofibers, desmin IFs lose their docking site at the nuclear membrane, leading to their collapse and aggregation in the vicinity and onto the surface of nuclei. The disconnection of nuclei from the IF network promotes alterations of nuclear morphology, dislocation of nuclei, decrease in their mobility and impaired mechanotransduction. Moreover, IF-uncoupling effects a structural reorganization of the nuclear interior, presenting as altered chromatin conformation and decreased gene expression. Note, for simplicity the IF network is depicted only in part. Yellow areas (A and B), perinuclear location of endophilin B.
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DDV438F9: Schematic model of cell organization and nuclear morphology typical of wild-type and P1-KO myofibers. (A) Each one of four major plectin isoforms expressed in myofibers is targeted to a different cellular compartment: P1 to the nuclear/ER membrane system, P1b to mitochondria, P1d to Z-disks and P1f to the sarcolemma. All of these isoforms recruit desmin IFs via their C-terminal IF-binding domain to these respective sites, thereby controlling IF network architecture and reinforcing the structural integrity of myofibers. P1 is predominantly localized at tail-like structures longitudinally extending from the nuclear equator. Desmin IFs recruited by P1 form a cage-like structure around nuclei, which holds nuclei under isometric tension, enabling their immediate response to mechanical stimuli. Ellipsoidally shaped, elongated nuclei are spatially distributed all along the myofiber. P1 targeting and nuclear docking occurs via nucleus-associated proteins, such as nesprin-3 and endophilin B. (B) In P1-deficient myofibers, desmin IFs lose their docking site at the nuclear membrane, leading to their collapse and aggregation in the vicinity and onto the surface of nuclei. The disconnection of nuclei from the IF network promotes alterations of nuclear morphology, dislocation of nuclei, decrease in their mobility and impaired mechanotransduction. Moreover, IF-uncoupling effects a structural reorganization of the nuclear interior, presenting as altered chromatin conformation and decreased gene expression. Note, for simplicity the IF network is depicted only in part. Yellow areas (A and B), perinuclear location of endophilin B.

Mentions: This study shows that P1, an ubiquitously expressed isoform of plectin, targets and anchors the desmin IF network to the outer membrane system of myonuclei. By phenotypically analyzing myofibers and myotubes derived from four genetically different mouse lines, including two isoform-specific knockout lines (P1-KO and P1b-KO), a muscle-restricted conditional (MCK/Cre) plectin knockout line and desmin- mice, we could show that P1 is essential for maintaining the typically spheroidal morphology and the regular distribution of myonuclei along the myofiber. As depicted in the schematic model presented in Figure 9, our data suggest that P1-mediated anchorage and integration into the desmin IF network provides myonuclei with a physical connection to the contractile apparatus (via P1d), the sarcoplasmic membrane (via P1f) and mitochondria (via P1b). As previously shown for IFs expressed in other cell types, such as fibroblasts, keratinocytes and endothelial cells (38–42), desmin IF networks form a cage-like structure around myonuclei and mechanically connect and integrate the nucleus with the cytoskeleton, other organelles as well as plasma membrane-associated structures. In this way, these elements are hold under isometric tension (prestress) and provide mechanical stiffness for the whole cell (43). The lack of P1 and the ensuing decoupling of nuclei from the IF network (formation of perinuclear desmin-positive protein aggregates) lead to an expansion in the volume of nuclei and a shape transition from ellipsoidal, as is typical of their pre-stressed (wild-type) state, to more spherical. It has been shown that disruption, mutations or deletions of IF proteins, including lamins, result in decreased mechanical stiffness of the cell but also in cell injury in response to mechanical stress and reduced mechanical activation of gene transcription (44–46). Because we found that the decoupling of IFs from the nuclear membrane as a consequence of P1 deficiency phenotypically manifests with nuclear aberrations similar to those observed in desmin- muscle, we conclude that nuclear docking of the IF network via plectin is indispensable for its role as mechanotransducer.Figure 9.


Plectin isoform 1-dependent nuclear docking of desmin networks affects myonuclear architecture and expression of mechanotransducers.

Staszewska I, Fischer I, Wiche G - Hum. Mol. Genet. (2015)

Schematic model of cell organization and nuclear morphology typical of wild-type and P1-KO myofibers. (A) Each one of four major plectin isoforms expressed in myofibers is targeted to a different cellular compartment: P1 to the nuclear/ER membrane system, P1b to mitochondria, P1d to Z-disks and P1f to the sarcolemma. All of these isoforms recruit desmin IFs via their C-terminal IF-binding domain to these respective sites, thereby controlling IF network architecture and reinforcing the structural integrity of myofibers. P1 is predominantly localized at tail-like structures longitudinally extending from the nuclear equator. Desmin IFs recruited by P1 form a cage-like structure around nuclei, which holds nuclei under isometric tension, enabling their immediate response to mechanical stimuli. Ellipsoidally shaped, elongated nuclei are spatially distributed all along the myofiber. P1 targeting and nuclear docking occurs via nucleus-associated proteins, such as nesprin-3 and endophilin B. (B) In P1-deficient myofibers, desmin IFs lose their docking site at the nuclear membrane, leading to their collapse and aggregation in the vicinity and onto the surface of nuclei. The disconnection of nuclei from the IF network promotes alterations of nuclear morphology, dislocation of nuclei, decrease in their mobility and impaired mechanotransduction. Moreover, IF-uncoupling effects a structural reorganization of the nuclear interior, presenting as altered chromatin conformation and decreased gene expression. Note, for simplicity the IF network is depicted only in part. Yellow areas (A and B), perinuclear location of endophilin B.
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DDV438F9: Schematic model of cell organization and nuclear morphology typical of wild-type and P1-KO myofibers. (A) Each one of four major plectin isoforms expressed in myofibers is targeted to a different cellular compartment: P1 to the nuclear/ER membrane system, P1b to mitochondria, P1d to Z-disks and P1f to the sarcolemma. All of these isoforms recruit desmin IFs via their C-terminal IF-binding domain to these respective sites, thereby controlling IF network architecture and reinforcing the structural integrity of myofibers. P1 is predominantly localized at tail-like structures longitudinally extending from the nuclear equator. Desmin IFs recruited by P1 form a cage-like structure around nuclei, which holds nuclei under isometric tension, enabling their immediate response to mechanical stimuli. Ellipsoidally shaped, elongated nuclei are spatially distributed all along the myofiber. P1 targeting and nuclear docking occurs via nucleus-associated proteins, such as nesprin-3 and endophilin B. (B) In P1-deficient myofibers, desmin IFs lose their docking site at the nuclear membrane, leading to their collapse and aggregation in the vicinity and onto the surface of nuclei. The disconnection of nuclei from the IF network promotes alterations of nuclear morphology, dislocation of nuclei, decrease in their mobility and impaired mechanotransduction. Moreover, IF-uncoupling effects a structural reorganization of the nuclear interior, presenting as altered chromatin conformation and decreased gene expression. Note, for simplicity the IF network is depicted only in part. Yellow areas (A and B), perinuclear location of endophilin B.
Mentions: This study shows that P1, an ubiquitously expressed isoform of plectin, targets and anchors the desmin IF network to the outer membrane system of myonuclei. By phenotypically analyzing myofibers and myotubes derived from four genetically different mouse lines, including two isoform-specific knockout lines (P1-KO and P1b-KO), a muscle-restricted conditional (MCK/Cre) plectin knockout line and desmin- mice, we could show that P1 is essential for maintaining the typically spheroidal morphology and the regular distribution of myonuclei along the myofiber. As depicted in the schematic model presented in Figure 9, our data suggest that P1-mediated anchorage and integration into the desmin IF network provides myonuclei with a physical connection to the contractile apparatus (via P1d), the sarcoplasmic membrane (via P1f) and mitochondria (via P1b). As previously shown for IFs expressed in other cell types, such as fibroblasts, keratinocytes and endothelial cells (38–42), desmin IF networks form a cage-like structure around myonuclei and mechanically connect and integrate the nucleus with the cytoskeleton, other organelles as well as plasma membrane-associated structures. In this way, these elements are hold under isometric tension (prestress) and provide mechanical stiffness for the whole cell (43). The lack of P1 and the ensuing decoupling of nuclei from the IF network (formation of perinuclear desmin-positive protein aggregates) lead to an expansion in the volume of nuclei and a shape transition from ellipsoidal, as is typical of their pre-stressed (wild-type) state, to more spherical. It has been shown that disruption, mutations or deletions of IF proteins, including lamins, result in decreased mechanical stiffness of the cell but also in cell injury in response to mechanical stress and reduced mechanical activation of gene transcription (44–46). Because we found that the decoupling of IFs from the nuclear membrane as a consequence of P1 deficiency phenotypically manifests with nuclear aberrations similar to those observed in desmin- muscle, we conclude that nuclear docking of the IF network via plectin is indispensable for its role as mechanotransducer.Figure 9.

Bottom Line: We show that P1-mediated targeting of desmin IFs to myonuclei is essential for maintenance of their typically spheroidal architecture as well as their proper positioning and movement along the myofiber.Mechanistically, P1 is shown to specifically interact with the myonuclear membrane-associated (BAR domain-containing) protein endophilin B.Our results open a new perspective on cytoskeleton-nuclear crosstalk via specific cytolinker proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.

No MeSH data available.


Related in: MedlinePlus