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Putting things in place for fertilization: discovering roles for importin proteins in cell fate and spermatogenesis.

Loveland KL, Major AT, Butler R, Young JC, Jans DA, Miyamoto Y - Asian J. Androl. (2015 Jul-Aug)

Bottom Line: Knowledge of importin function has expanded substantially in regard to three key developmental systems: embryonic stem cells, muscle cells and the germ line.In the decade since the potential for regulated nucleocytoplasmic transport to contribute to spermatogenesis was proposed, we and others have shown that the importins that ferry transcription factors into the nucleus perform additional roles, which control cell fate.These studies of germline genesis illuminate new ways in which importin proteins govern cellular differentiation, including via directing proteins to distinct intracellular compartments and by determining cellular stress responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology;Department of Anatomy and Developmental Biology, Monash University; Hudson Institute of Medical Research, Monash Medical Centre; School of Clinical Sciences, Monash University, Clayton, VIC, Australia, .

ABSTRACT
Importin proteins were originally characterized for their central role in protein transport through the nuclear pores, the only intracellular entry to the nucleus. This vital function must be tightly regulated to control access by transcription factors and other nuclear proteins to genomic DNA, to achieve appropriate modulation of cellular behaviors affecting cell fate. Importin-mediated nucleocytoplasmic transport relies on their specific recognition of cargoes, with each importin binding to distinct and overlapping protein subsets. Knowledge of importin function has expanded substantially in regard to three key developmental systems: embryonic stem cells, muscle cells and the germ line. In the decade since the potential for regulated nucleocytoplasmic transport to contribute to spermatogenesis was proposed, we and others have shown that the importins that ferry transcription factors into the nucleus perform additional roles, which control cell fate. This review presents key findings from studies of mammalian spermatogenesis that reveal potential new pathways by which male fertility and infertility arise. These studies of germline genesis illuminate new ways in which importin proteins govern cellular differentiation, including via directing proteins to distinct intracellular compartments and by determining cellular stress responses.

No MeSH data available.


Related in: MedlinePlus

Synthesis of importin proteins that function in nucleocytoplasmic transport is developmentally regulated during spermatogenesis. (a) Classical nucleocytoplasmic transport. Proteins larger than 40 kDa that undertake key functions in the nucleus require active transport through the nuclear pore complex (NPC). For many proteins, such movement is mediated by members of the importin family. (i) Importin α (IMPα) proteins act as receptors that recognize nuclear localization signal (NLS) motifs in the cargo proteins. (ii) Complex formation with importin β1 (IMPβ) allows the passage of cargo molecules through the nuclear pore. Other IMPβ family members, including IPO5, can mediate IMPα-independent transport. (iii) Once in the nucleus, the complex is dissociated, releasing the cargo protein to play its nuclear role, and the importin proteins are recycled back into the cytoplasm. Maintenance of the RanGDP/GTP gradient, in which RanGTP is high in the nucleus, is critical for regulated nucleocytoplasmic transport. (b) Three clades of importin α proteins. The importin α (IMPα) proteins are classified into three distinct subgroups based on percentage identity, as indicated. Despite this classification, there is significant (50%) identity across subgroups. (c) IMPα proteins harbor multiple domains that mediate cargo binding. The classical localization signal (cNLS) classes recognized by the six murine IMPa cargo proteins correspond to either mono- or bipartite sequences of 8–10 basic residue-enriched amino acids. These sequences occur in the major and/or minor binding grooves within the ARM repeat motifs and can be identified with reasonable accuracy by the cNLS Mapper algorithm.42 However, cargo binding to a C-terminal “acidic” domain has been identified.13 This domain was recently examined through a new algorithm designed specifically to identify common amino acid sequence patterns within the set of binding proteins that mediate binding to the C-terminus of IMPα proteins. This newly defined motif has been designated iCBS, for ‘IMPα C-terminal binding segment’.32 IBB, importin β binding domain. ARM, armadillo. (d) Importins are highly regulated at both the RNA and protein level, and each has a specific pattern of expression that correlates with spermatogenic progression. The major developmental stages of spermatogenesis are shown, with the mitotic, meiotic, and spermiogenic phases indicated. Based on studies in rodent models, importin transcript (solid bars) and protein (hatched bars) levels are presented by shading intensity, indicating a potential role as drivers of germ cell development through adult spermatogenesis. IMPα3 and IMPα4 are noted, as despite their high degree of similarity (80%), they are each detected in different stages of spermatogenesis, and in different subcellular compartments.
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Figure 1: Synthesis of importin proteins that function in nucleocytoplasmic transport is developmentally regulated during spermatogenesis. (a) Classical nucleocytoplasmic transport. Proteins larger than 40 kDa that undertake key functions in the nucleus require active transport through the nuclear pore complex (NPC). For many proteins, such movement is mediated by members of the importin family. (i) Importin α (IMPα) proteins act as receptors that recognize nuclear localization signal (NLS) motifs in the cargo proteins. (ii) Complex formation with importin β1 (IMPβ) allows the passage of cargo molecules through the nuclear pore. Other IMPβ family members, including IPO5, can mediate IMPα-independent transport. (iii) Once in the nucleus, the complex is dissociated, releasing the cargo protein to play its nuclear role, and the importin proteins are recycled back into the cytoplasm. Maintenance of the RanGDP/GTP gradient, in which RanGTP is high in the nucleus, is critical for regulated nucleocytoplasmic transport. (b) Three clades of importin α proteins. The importin α (IMPα) proteins are classified into three distinct subgroups based on percentage identity, as indicated. Despite this classification, there is significant (50%) identity across subgroups. (c) IMPα proteins harbor multiple domains that mediate cargo binding. The classical localization signal (cNLS) classes recognized by the six murine IMPa cargo proteins correspond to either mono- or bipartite sequences of 8–10 basic residue-enriched amino acids. These sequences occur in the major and/or minor binding grooves within the ARM repeat motifs and can be identified with reasonable accuracy by the cNLS Mapper algorithm.42 However, cargo binding to a C-terminal “acidic” domain has been identified.13 This domain was recently examined through a new algorithm designed specifically to identify common amino acid sequence patterns within the set of binding proteins that mediate binding to the C-terminus of IMPα proteins. This newly defined motif has been designated iCBS, for ‘IMPα C-terminal binding segment’.32 IBB, importin β binding domain. ARM, armadillo. (d) Importins are highly regulated at both the RNA and protein level, and each has a specific pattern of expression that correlates with spermatogenic progression. The major developmental stages of spermatogenesis are shown, with the mitotic, meiotic, and spermiogenic phases indicated. Based on studies in rodent models, importin transcript (solid bars) and protein (hatched bars) levels are presented by shading intensity, indicating a potential role as drivers of germ cell development through adult spermatogenesis. IMPα3 and IMPα4 are noted, as despite their high degree of similarity (80%), they are each detected in different stages of spermatogenesis, and in different subcellular compartments.

Mentions: The importins are further categorized into importin αs and importin βs, based on their structural and functional features. In classical nucleocytoplasmic transport, an importin α protein functions as an adapter by linking cargo proteins to an importin β1 molecule. This complex forms in the cytoplasm in an environment of high RanGDP levels. Each importin α functions by recognizing a nuclear localization signal (NLS) in cargoes, typically one or two stretches of 8–10 amino acids containing a high proportion of basic residues, termed monopartite and bipartite NLSs, respectively (Figure 1ai). The binding of a cargo molecule by importin α allows it to bind to importin β1, creating a trimeric complex (Figure 1aii). Importin β1 binds to the NUPs lining the nuclear pore to mediate translocation of this complex into the nucleus. In the presence of high levels of RanGTP within the nucleus, the transport complex is dissociated (Figure 1aiii). Both importin α and β1 proteins are recycled to the cytoplasm by independent means, in readiness to complete another round of transport, after the cargo is released to perform its nuclear function.


Putting things in place for fertilization: discovering roles for importin proteins in cell fate and spermatogenesis.

Loveland KL, Major AT, Butler R, Young JC, Jans DA, Miyamoto Y - Asian J. Androl. (2015 Jul-Aug)

Synthesis of importin proteins that function in nucleocytoplasmic transport is developmentally regulated during spermatogenesis. (a) Classical nucleocytoplasmic transport. Proteins larger than 40 kDa that undertake key functions in the nucleus require active transport through the nuclear pore complex (NPC). For many proteins, such movement is mediated by members of the importin family. (i) Importin α (IMPα) proteins act as receptors that recognize nuclear localization signal (NLS) motifs in the cargo proteins. (ii) Complex formation with importin β1 (IMPβ) allows the passage of cargo molecules through the nuclear pore. Other IMPβ family members, including IPO5, can mediate IMPα-independent transport. (iii) Once in the nucleus, the complex is dissociated, releasing the cargo protein to play its nuclear role, and the importin proteins are recycled back into the cytoplasm. Maintenance of the RanGDP/GTP gradient, in which RanGTP is high in the nucleus, is critical for regulated nucleocytoplasmic transport. (b) Three clades of importin α proteins. The importin α (IMPα) proteins are classified into three distinct subgroups based on percentage identity, as indicated. Despite this classification, there is significant (50%) identity across subgroups. (c) IMPα proteins harbor multiple domains that mediate cargo binding. The classical localization signal (cNLS) classes recognized by the six murine IMPa cargo proteins correspond to either mono- or bipartite sequences of 8–10 basic residue-enriched amino acids. These sequences occur in the major and/or minor binding grooves within the ARM repeat motifs and can be identified with reasonable accuracy by the cNLS Mapper algorithm.42 However, cargo binding to a C-terminal “acidic” domain has been identified.13 This domain was recently examined through a new algorithm designed specifically to identify common amino acid sequence patterns within the set of binding proteins that mediate binding to the C-terminus of IMPα proteins. This newly defined motif has been designated iCBS, for ‘IMPα C-terminal binding segment’.32 IBB, importin β binding domain. ARM, armadillo. (d) Importins are highly regulated at both the RNA and protein level, and each has a specific pattern of expression that correlates with spermatogenic progression. The major developmental stages of spermatogenesis are shown, with the mitotic, meiotic, and spermiogenic phases indicated. Based on studies in rodent models, importin transcript (solid bars) and protein (hatched bars) levels are presented by shading intensity, indicating a potential role as drivers of germ cell development through adult spermatogenesis. IMPα3 and IMPα4 are noted, as despite their high degree of similarity (80%), they are each detected in different stages of spermatogenesis, and in different subcellular compartments.
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Figure 1: Synthesis of importin proteins that function in nucleocytoplasmic transport is developmentally regulated during spermatogenesis. (a) Classical nucleocytoplasmic transport. Proteins larger than 40 kDa that undertake key functions in the nucleus require active transport through the nuclear pore complex (NPC). For many proteins, such movement is mediated by members of the importin family. (i) Importin α (IMPα) proteins act as receptors that recognize nuclear localization signal (NLS) motifs in the cargo proteins. (ii) Complex formation with importin β1 (IMPβ) allows the passage of cargo molecules through the nuclear pore. Other IMPβ family members, including IPO5, can mediate IMPα-independent transport. (iii) Once in the nucleus, the complex is dissociated, releasing the cargo protein to play its nuclear role, and the importin proteins are recycled back into the cytoplasm. Maintenance of the RanGDP/GTP gradient, in which RanGTP is high in the nucleus, is critical for regulated nucleocytoplasmic transport. (b) Three clades of importin α proteins. The importin α (IMPα) proteins are classified into three distinct subgroups based on percentage identity, as indicated. Despite this classification, there is significant (50%) identity across subgroups. (c) IMPα proteins harbor multiple domains that mediate cargo binding. The classical localization signal (cNLS) classes recognized by the six murine IMPa cargo proteins correspond to either mono- or bipartite sequences of 8–10 basic residue-enriched amino acids. These sequences occur in the major and/or minor binding grooves within the ARM repeat motifs and can be identified with reasonable accuracy by the cNLS Mapper algorithm.42 However, cargo binding to a C-terminal “acidic” domain has been identified.13 This domain was recently examined through a new algorithm designed specifically to identify common amino acid sequence patterns within the set of binding proteins that mediate binding to the C-terminus of IMPα proteins. This newly defined motif has been designated iCBS, for ‘IMPα C-terminal binding segment’.32 IBB, importin β binding domain. ARM, armadillo. (d) Importins are highly regulated at both the RNA and protein level, and each has a specific pattern of expression that correlates with spermatogenic progression. The major developmental stages of spermatogenesis are shown, with the mitotic, meiotic, and spermiogenic phases indicated. Based on studies in rodent models, importin transcript (solid bars) and protein (hatched bars) levels are presented by shading intensity, indicating a potential role as drivers of germ cell development through adult spermatogenesis. IMPα3 and IMPα4 are noted, as despite their high degree of similarity (80%), they are each detected in different stages of spermatogenesis, and in different subcellular compartments.
Mentions: The importins are further categorized into importin αs and importin βs, based on their structural and functional features. In classical nucleocytoplasmic transport, an importin α protein functions as an adapter by linking cargo proteins to an importin β1 molecule. This complex forms in the cytoplasm in an environment of high RanGDP levels. Each importin α functions by recognizing a nuclear localization signal (NLS) in cargoes, typically one or two stretches of 8–10 amino acids containing a high proportion of basic residues, termed monopartite and bipartite NLSs, respectively (Figure 1ai). The binding of a cargo molecule by importin α allows it to bind to importin β1, creating a trimeric complex (Figure 1aii). Importin β1 binds to the NUPs lining the nuclear pore to mediate translocation of this complex into the nucleus. In the presence of high levels of RanGTP within the nucleus, the transport complex is dissociated (Figure 1aiii). Both importin α and β1 proteins are recycled to the cytoplasm by independent means, in readiness to complete another round of transport, after the cargo is released to perform its nuclear function.

Bottom Line: Knowledge of importin function has expanded substantially in regard to three key developmental systems: embryonic stem cells, muscle cells and the germ line.In the decade since the potential for regulated nucleocytoplasmic transport to contribute to spermatogenesis was proposed, we and others have shown that the importins that ferry transcription factors into the nucleus perform additional roles, which control cell fate.These studies of germline genesis illuminate new ways in which importin proteins govern cellular differentiation, including via directing proteins to distinct intracellular compartments and by determining cellular stress responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology;Department of Anatomy and Developmental Biology, Monash University; Hudson Institute of Medical Research, Monash Medical Centre; School of Clinical Sciences, Monash University, Clayton, VIC, Australia, .

ABSTRACT
Importin proteins were originally characterized for their central role in protein transport through the nuclear pores, the only intracellular entry to the nucleus. This vital function must be tightly regulated to control access by transcription factors and other nuclear proteins to genomic DNA, to achieve appropriate modulation of cellular behaviors affecting cell fate. Importin-mediated nucleocytoplasmic transport relies on their specific recognition of cargoes, with each importin binding to distinct and overlapping protein subsets. Knowledge of importin function has expanded substantially in regard to three key developmental systems: embryonic stem cells, muscle cells and the germ line. In the decade since the potential for regulated nucleocytoplasmic transport to contribute to spermatogenesis was proposed, we and others have shown that the importins that ferry transcription factors into the nucleus perform additional roles, which control cell fate. This review presents key findings from studies of mammalian spermatogenesis that reveal potential new pathways by which male fertility and infertility arise. These studies of germline genesis illuminate new ways in which importin proteins govern cellular differentiation, including via directing proteins to distinct intracellular compartments and by determining cellular stress responses.

No MeSH data available.


Related in: MedlinePlus