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An Importin Code in neuronal transport from synapse-to-nucleus?

Lever MB, Karpova A, Kreutz MR - Front Mol Neurosci (2015)

View Article: PubMed Central - PubMed

Affiliation: RG Neuroplasticity, Leibniz Institute for Neurobiology Magdeburg, Germany.

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An emerging system capable of transducing signals that likely influence transcription is synapse-to-nucleus macromolecular protein shuttling, in which synaptic proteins are relayed to the nucleus in a complex with importins (also referred to by their gene name: Karyopherins/KPNs) and molecular motors such as dynein (Jordan and Kreutz,, Figure 1C)... Despite a central position in a neuronal process capable of altering transcription, there is a dearth of research into importin function in neurites... In this opinion paper we summarize neuronal importin understanding to date, present novel ideas relating to their neuronal function and highlight the reductionist nature of the classical description of nuclear import with the specific example that complex composition is likely much more intricate than is being considered... There are several exceptions to the classical description (to be discussed) but the involvement of importins in the nuclear import of cargo proteins is clear... Importins exhibit a widespread distribution in dendrites, axons and synapses (Thompson et al., ; Jeffrey et al., ; Higashi-Kovtun et al., )... Evidence for importins having unique interacting partners in neurons comes from the finding that knockdown of importin-α1 results in improper nuclear accumulation of PER in drosophila neurons, whereas importin-α2 or importin-α3 knockdown did not have the same effect (Jang et al., )... This was first shown with the finding that importin-α and importin-β isoforms interact with the retrograde molecular motor dynein in the axoplasm of rats and that nerve injury induces increased association of importin-β 1 with dynein, presumably to rapidly convey the new neuronal information to the nucleus using cargo proteins such as ERK1-2 (Hanz et al., ; Perlson et al., )... Because of homology to importin-β in both of the above examples, the authors predict that the NICSI replaces the importin-β in the transport complex... However, Jang et al. found that removal of the IBB domain of importin-α1 did not prevent binding of importin-α1 to TIM1, suggesting that NICSIs act as cargos to importin-α(s) and that transport complexes could feasibly be composed of importin-α, NICSI and cargo with or without an importin-β... Based on sequence similarities of over 20% identical to importin-β 1 (importin-β family members typically have between 15 and 20% homology) there are at least 5 more easily-identifiable NICSIs (MIP, BRAT1, TNPO2, STK36, SPAG6) (elucidated via BLAST search on NCBI database)... As TIM1 and Htt do not meet this criterion, we expect that there are more yet-to-be-discovered NICSIs based on evolutionary homology and primary/secondary/tertiary structures... Assuming that some importin-α isoforms can combine with each other in neurons and that there are a number of NICSIs that are components of synapse-to-nucleus complexes, the number of potential importin-β, importin-α, importin-α and NICSI combinations becomes huge (in the order of thousands)... We do not expect that all of the thousands of potential importin combinations exist but we suggest that there is a much greater number of importin combinations than is currently being portrayed by the classical description (Figure 1C4)... Whilst the hypothesis that importins function as adaptor proteins in the mediation of cargo-specific synapse-to-nucleus transport for key brain processes such as long-term forms of synaptic plasticity is informative and useful, it has several important caveats: Non-canonical importin functions are emerging and the role of importins in transport cargo specificity is likely being underestimated... The Importin Code best depicts the grand cargo specificity that importins provide to tightly regulate synaptic protein selection for nuclear import that ultimately governs cellular phenotypes.

No MeSH data available.


Related in: MedlinePlus

Importin structures, canonical and non-caconocal nuclear import and The Importin Code. (A) The general domain structure of importin-α and importin-β (1) importin-α is composed of an N-terminus importin-β binding domain (IBB) followed by 10 armadillo (ARM) repeats- cargo proteins typically bind at either ARMs 2–4 (monopartite binding at the major site) or at ARMs 2–4 and ARMs 7–8 (bipartite binding at the major and minor sites, respectively). Importin-β isoforms are comprised of 19-20 HEAT repeats. (B) Nuclear import in neurons from the soma, axons and dendrites/synapses: all of which may incorporate The Importin Code and converge in the nucleus where transcriptional alterations can be induced. (1) The classical description of nuclear import. The trimeric complex (importin-α, importin-β and cargo) translocates from the soma, across the nuclear pore complex (NPC) at the nuclear envelope (NE) and into the nucleus where Ran-GTP binds importin-β, liberating components of the complex. Importin-β likely transports back to the cytoplasm, whereas the cargo and importin-α may perform nuclear functions. (2) Nuclear import from axons. A complex composed of importin-α, importin-β and cargo (trimeric complex shown) is attached to microtubules via the molecular motor dynein, which drives the complex to the nucleus. (3) Synapse-to-nucleus transport. Importin-α and cargo proteins likely assemble in the synapse and are transported to the nucleus along microtubules by the molecular motor dynein. Importin-β is incorporated into the complex prior to NPC passage. (C) The Importin Code. (1) Classically described importin codes: the trimeric complex and importin-β alone with a cargo, (2) importin codes that are frequently attached as caveats to the classically described complex compositions. Importin-α can mediate cargo transport alone, 2 importin-β (s) can mediate transport, cargos can execute their own nuclear import independently of importins and importins may carry 2 cargos. (3) Possible importin codes incorporating the newly proposed non-importin family member cargo-specific importins (NICSIs). (4) Highly speculative importin codes based on the possibility of NICSI involvement in nuclear import and on potential importin-α dimers.
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Figure 1: Importin structures, canonical and non-caconocal nuclear import and The Importin Code. (A) The general domain structure of importin-α and importin-β (1) importin-α is composed of an N-terminus importin-β binding domain (IBB) followed by 10 armadillo (ARM) repeats- cargo proteins typically bind at either ARMs 2–4 (monopartite binding at the major site) or at ARMs 2–4 and ARMs 7–8 (bipartite binding at the major and minor sites, respectively). Importin-β isoforms are comprised of 19-20 HEAT repeats. (B) Nuclear import in neurons from the soma, axons and dendrites/synapses: all of which may incorporate The Importin Code and converge in the nucleus where transcriptional alterations can be induced. (1) The classical description of nuclear import. The trimeric complex (importin-α, importin-β and cargo) translocates from the soma, across the nuclear pore complex (NPC) at the nuclear envelope (NE) and into the nucleus where Ran-GTP binds importin-β, liberating components of the complex. Importin-β likely transports back to the cytoplasm, whereas the cargo and importin-α may perform nuclear functions. (2) Nuclear import from axons. A complex composed of importin-α, importin-β and cargo (trimeric complex shown) is attached to microtubules via the molecular motor dynein, which drives the complex to the nucleus. (3) Synapse-to-nucleus transport. Importin-α and cargo proteins likely assemble in the synapse and are transported to the nucleus along microtubules by the molecular motor dynein. Importin-β is incorporated into the complex prior to NPC passage. (C) The Importin Code. (1) Classically described importin codes: the trimeric complex and importin-β alone with a cargo, (2) importin codes that are frequently attached as caveats to the classically described complex compositions. Importin-α can mediate cargo transport alone, 2 importin-β (s) can mediate transport, cargos can execute their own nuclear import independently of importins and importins may carry 2 cargos. (3) Possible importin codes incorporating the newly proposed non-importin family member cargo-specific importins (NICSIs). (4) Highly speculative importin codes based on the possibility of NICSI involvement in nuclear import and on potential importin-α dimers.

Mentions: The principle cells of the brain- neurons- express more genes than any other cell type. As many rudimentary processes of the brain, such as long-lasting changes in synaptic efficacy, involve alterations to the expression of genes, the characterisation of proteins and processes that influence transcription is a high priority in neuroscience. An emerging system capable of transducing signals that likely influence transcription is synapse-to-nucleus macromolecular protein shuttling, in which synaptic proteins are relayed to the nucleus in a complex with importins (also referred to by their gene name: Karyopherins/KPNs) and molecular motors such as dynein (Jordan and Kreutz, 2009, Figure 1C). Despite a central position in a neuronal process capable of altering transcription, there is a dearth of research into importin function in neurites. In this opinion paper we summarize neuronal importin understanding to date, present novel ideas relating to their neuronal function and highlight the reductionist nature of the classical description of nuclear import with the specific example that complex composition is likely much more intricate than is being considered.


An Importin Code in neuronal transport from synapse-to-nucleus?

Lever MB, Karpova A, Kreutz MR - Front Mol Neurosci (2015)

Importin structures, canonical and non-caconocal nuclear import and The Importin Code. (A) The general domain structure of importin-α and importin-β (1) importin-α is composed of an N-terminus importin-β binding domain (IBB) followed by 10 armadillo (ARM) repeats- cargo proteins typically bind at either ARMs 2–4 (monopartite binding at the major site) or at ARMs 2–4 and ARMs 7–8 (bipartite binding at the major and minor sites, respectively). Importin-β isoforms are comprised of 19-20 HEAT repeats. (B) Nuclear import in neurons from the soma, axons and dendrites/synapses: all of which may incorporate The Importin Code and converge in the nucleus where transcriptional alterations can be induced. (1) The classical description of nuclear import. The trimeric complex (importin-α, importin-β and cargo) translocates from the soma, across the nuclear pore complex (NPC) at the nuclear envelope (NE) and into the nucleus where Ran-GTP binds importin-β, liberating components of the complex. Importin-β likely transports back to the cytoplasm, whereas the cargo and importin-α may perform nuclear functions. (2) Nuclear import from axons. A complex composed of importin-α, importin-β and cargo (trimeric complex shown) is attached to microtubules via the molecular motor dynein, which drives the complex to the nucleus. (3) Synapse-to-nucleus transport. Importin-α and cargo proteins likely assemble in the synapse and are transported to the nucleus along microtubules by the molecular motor dynein. Importin-β is incorporated into the complex prior to NPC passage. (C) The Importin Code. (1) Classically described importin codes: the trimeric complex and importin-β alone with a cargo, (2) importin codes that are frequently attached as caveats to the classically described complex compositions. Importin-α can mediate cargo transport alone, 2 importin-β (s) can mediate transport, cargos can execute their own nuclear import independently of importins and importins may carry 2 cargos. (3) Possible importin codes incorporating the newly proposed non-importin family member cargo-specific importins (NICSIs). (4) Highly speculative importin codes based on the possibility of NICSI involvement in nuclear import and on potential importin-α dimers.
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Related In: Results  -  Collection

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Show All Figures
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Figure 1: Importin structures, canonical and non-caconocal nuclear import and The Importin Code. (A) The general domain structure of importin-α and importin-β (1) importin-α is composed of an N-terminus importin-β binding domain (IBB) followed by 10 armadillo (ARM) repeats- cargo proteins typically bind at either ARMs 2–4 (monopartite binding at the major site) or at ARMs 2–4 and ARMs 7–8 (bipartite binding at the major and minor sites, respectively). Importin-β isoforms are comprised of 19-20 HEAT repeats. (B) Nuclear import in neurons from the soma, axons and dendrites/synapses: all of which may incorporate The Importin Code and converge in the nucleus where transcriptional alterations can be induced. (1) The classical description of nuclear import. The trimeric complex (importin-α, importin-β and cargo) translocates from the soma, across the nuclear pore complex (NPC) at the nuclear envelope (NE) and into the nucleus where Ran-GTP binds importin-β, liberating components of the complex. Importin-β likely transports back to the cytoplasm, whereas the cargo and importin-α may perform nuclear functions. (2) Nuclear import from axons. A complex composed of importin-α, importin-β and cargo (trimeric complex shown) is attached to microtubules via the molecular motor dynein, which drives the complex to the nucleus. (3) Synapse-to-nucleus transport. Importin-α and cargo proteins likely assemble in the synapse and are transported to the nucleus along microtubules by the molecular motor dynein. Importin-β is incorporated into the complex prior to NPC passage. (C) The Importin Code. (1) Classically described importin codes: the trimeric complex and importin-β alone with a cargo, (2) importin codes that are frequently attached as caveats to the classically described complex compositions. Importin-α can mediate cargo transport alone, 2 importin-β (s) can mediate transport, cargos can execute their own nuclear import independently of importins and importins may carry 2 cargos. (3) Possible importin codes incorporating the newly proposed non-importin family member cargo-specific importins (NICSIs). (4) Highly speculative importin codes based on the possibility of NICSI involvement in nuclear import and on potential importin-α dimers.
Mentions: The principle cells of the brain- neurons- express more genes than any other cell type. As many rudimentary processes of the brain, such as long-lasting changes in synaptic efficacy, involve alterations to the expression of genes, the characterisation of proteins and processes that influence transcription is a high priority in neuroscience. An emerging system capable of transducing signals that likely influence transcription is synapse-to-nucleus macromolecular protein shuttling, in which synaptic proteins are relayed to the nucleus in a complex with importins (also referred to by their gene name: Karyopherins/KPNs) and molecular motors such as dynein (Jordan and Kreutz, 2009, Figure 1C). Despite a central position in a neuronal process capable of altering transcription, there is a dearth of research into importin function in neurites. In this opinion paper we summarize neuronal importin understanding to date, present novel ideas relating to their neuronal function and highlight the reductionist nature of the classical description of nuclear import with the specific example that complex composition is likely much more intricate than is being considered.

View Article: PubMed Central - PubMed

Affiliation: RG Neuroplasticity, Leibniz Institute for Neurobiology Magdeburg, Germany.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

An emerging system capable of transducing signals that likely influence transcription is synapse-to-nucleus macromolecular protein shuttling, in which synaptic proteins are relayed to the nucleus in a complex with importins (also referred to by their gene name: Karyopherins/KPNs) and molecular motors such as dynein (Jordan and Kreutz,, Figure 1C)... Despite a central position in a neuronal process capable of altering transcription, there is a dearth of research into importin function in neurites... In this opinion paper we summarize neuronal importin understanding to date, present novel ideas relating to their neuronal function and highlight the reductionist nature of the classical description of nuclear import with the specific example that complex composition is likely much more intricate than is being considered... There are several exceptions to the classical description (to be discussed) but the involvement of importins in the nuclear import of cargo proteins is clear... Importins exhibit a widespread distribution in dendrites, axons and synapses (Thompson et al., ; Jeffrey et al., ; Higashi-Kovtun et al., )... Evidence for importins having unique interacting partners in neurons comes from the finding that knockdown of importin-α1 results in improper nuclear accumulation of PER in drosophila neurons, whereas importin-α2 or importin-α3 knockdown did not have the same effect (Jang et al., )... This was first shown with the finding that importin-α and importin-β isoforms interact with the retrograde molecular motor dynein in the axoplasm of rats and that nerve injury induces increased association of importin-β 1 with dynein, presumably to rapidly convey the new neuronal information to the nucleus using cargo proteins such as ERK1-2 (Hanz et al., ; Perlson et al., )... Because of homology to importin-β in both of the above examples, the authors predict that the NICSI replaces the importin-β in the transport complex... However, Jang et al. found that removal of the IBB domain of importin-α1 did not prevent binding of importin-α1 to TIM1, suggesting that NICSIs act as cargos to importin-α(s) and that transport complexes could feasibly be composed of importin-α, NICSI and cargo with or without an importin-β... Based on sequence similarities of over 20% identical to importin-β 1 (importin-β family members typically have between 15 and 20% homology) there are at least 5 more easily-identifiable NICSIs (MIP, BRAT1, TNPO2, STK36, SPAG6) (elucidated via BLAST search on NCBI database)... As TIM1 and Htt do not meet this criterion, we expect that there are more yet-to-be-discovered NICSIs based on evolutionary homology and primary/secondary/tertiary structures... Assuming that some importin-α isoforms can combine with each other in neurons and that there are a number of NICSIs that are components of synapse-to-nucleus complexes, the number of potential importin-β, importin-α, importin-α and NICSI combinations becomes huge (in the order of thousands)... We do not expect that all of the thousands of potential importin combinations exist but we suggest that there is a much greater number of importin combinations than is currently being portrayed by the classical description (Figure 1C4)... Whilst the hypothesis that importins function as adaptor proteins in the mediation of cargo-specific synapse-to-nucleus transport for key brain processes such as long-term forms of synaptic plasticity is informative and useful, it has several important caveats: Non-canonical importin functions are emerging and the role of importins in transport cargo specificity is likely being underestimated... The Importin Code best depicts the grand cargo specificity that importins provide to tightly regulate synaptic protein selection for nuclear import that ultimately governs cellular phenotypes.

No MeSH data available.


Related in: MedlinePlus