Limits...
The role of the molecular chaperone heat shock protein A2 (HSPA2) in regulating human sperm-egg recognition.

Nixon B, Bromfield EG, Dun MD, Redgrove KA, McLaughlin EA, Aitken RJ - Asian J. Androl. (2015 Jul-Aug)

Bottom Line: Although this unique cellular interaction can now be readily by-passed by assisted reproductive strategies such as intracytoplasmic sperm injection (ICSI), recent large-scale epidemiological studies have encouraged the cautious use of this technology and highlighted the need for further research into the mechanisms responsible for defective sperm-egg recognition.While the factors responsible for the regulation of these sequential maturational events are undoubtedly complex, emerging research has identified the molecular chaperone, heat shock protein A2 (HSPA2), as a key regulator of these events in human spermatozoa.HSPA2 is a testis-enriched member of the 70 kDa heat shock protein family that promotes the folding, transport, and assembly of protein complexes and has been positively correlated with in vitro fertilization (IVF) success.

View Article: PubMed Central - PubMed

Affiliation: Priority Research Centre in Reproductive Science; Priority Research Centre in Chemical Biology, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.

ABSTRACT
One of the most common lesions present in the spermatozoa of human infertility patients is an idiopathic failure of sperm-egg recognition. Although this unique cellular interaction can now be readily by-passed by assisted reproductive strategies such as intracytoplasmic sperm injection (ICSI), recent large-scale epidemiological studies have encouraged the cautious use of this technology and highlighted the need for further research into the mechanisms responsible for defective sperm-egg recognition. Previous work in this field has established that the sperm domains responsible for oocyte interaction are formed during spermatogenesis prior to being dynamically modified during epididymal maturation and capacitation in female reproductive tract. While the factors responsible for the regulation of these sequential maturational events are undoubtedly complex, emerging research has identified the molecular chaperone, heat shock protein A2 (HSPA2), as a key regulator of these events in human spermatozoa. HSPA2 is a testis-enriched member of the 70 kDa heat shock protein family that promotes the folding, transport, and assembly of protein complexes and has been positively correlated with in vitro fertilization (IVF) success. Furthermore, reduced expression of HSPA2 from the human sperm proteome leads to an impaired capacity for cumulus matrix dispersal, sperm-egg recognition and fertilization following both IVF and ICSI. In this review, we consider the evidence supporting the role of HSPA2 in sperm function and explore the potential mechanisms by which it is depleted in the spermatozoa of infertile patients. Such information offers novel insights into the molecular mechanisms governing sperm function.

No MeSH data available.


Related in: MedlinePlus

Mechanisms underpinning the loss of heat shock protein A2 (HSPA2) from the spermatozoa of infertile patients. Although the mechanism(s) underpinning the selective loss of HSPA2 from the differentiating gametes of infertile patients is currently unknown, several possibilities have been raised. These include: (a) genetic mutations in the encoding Hspa2 gene, (b) epigenetic regulation of Hspa2 gene expression, and/or (c) perturbations in protein expression/stability arising from exposure of developing germ cells to oxidative stress. With regard to the latter it is possible the oxidative attack could act directly to damage the Hspa2 gene or mRNA transcript. Alternatively, the HSPA2 protein itself may be targeted for destruction following adduction by electrophilic aldehydes generated as a result of reactive oxygen species-induced lipid peroxidation. Such insults are known to lead ubiquitin (Ub)-dependent degradation via proteasomal or lysosomal pathways.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492046&req=5

Figure 2: Mechanisms underpinning the loss of heat shock protein A2 (HSPA2) from the spermatozoa of infertile patients. Although the mechanism(s) underpinning the selective loss of HSPA2 from the differentiating gametes of infertile patients is currently unknown, several possibilities have been raised. These include: (a) genetic mutations in the encoding Hspa2 gene, (b) epigenetic regulation of Hspa2 gene expression, and/or (c) perturbations in protein expression/stability arising from exposure of developing germ cells to oxidative stress. With regard to the latter it is possible the oxidative attack could act directly to damage the Hspa2 gene or mRNA transcript. Alternatively, the HSPA2 protein itself may be targeted for destruction following adduction by electrophilic aldehydes generated as a result of reactive oxygen species-induced lipid peroxidation. Such insults are known to lead ubiquitin (Ub)-dependent degradation via proteasomal or lysosomal pathways.

Mentions: Finally, as an alternative to mRNA damage, it is also possible that the lack of HSPA2 seen in spermatozoa of infertile patients may arise from a mechanism involving the targeted destruction of the protein itself. Consistent with this notion, recent work from our laboratory has shown that electrophilic aldehydes, such as 4-hydroxynonenal (4HNE), generated as a result of reactive oxygen species-induced lipid peroxidation are readily capable of adducting proteins localized within the head of human spermatozoa.89 Furthermore, peptides belonging to HSP70 family members have been identified among the major 4HNE alkylated targets in these damaged cells.89 While the primary impact of 4HNE covalently binding to proteins in mature spermatozoa is likely to involve conformational changes and/or aggregation leading to disruption of their functionality,90 it may have a more pronounced effect in developing germ cells (Figure 2). Indeed in tissues such as the testis, which possess an intrinsic ubiquitin-proteasome system, such insults commonly lead to the activation of a protein degradation cascade that selectively eliminates damaged proteins in an effort to mitigate the impact of oxidative injury.919293 Alternative, ubiquitin-dependent lysosomal degradation mechanisms have also recently been reported for 4HNE-modified proteins.94 Whether such mechanisms underpin the loss of susceptible proteins such as HSPA2 from maturing spermatozoa remains to be established. Similarly, it also has yet to be investigated whether aberrant expression of BAT3 might contribute to this phenotype through accelerated degradation of HSPA254 during human spermatogenesis.


The role of the molecular chaperone heat shock protein A2 (HSPA2) in regulating human sperm-egg recognition.

Nixon B, Bromfield EG, Dun MD, Redgrove KA, McLaughlin EA, Aitken RJ - Asian J. Androl. (2015 Jul-Aug)

Mechanisms underpinning the loss of heat shock protein A2 (HSPA2) from the spermatozoa of infertile patients. Although the mechanism(s) underpinning the selective loss of HSPA2 from the differentiating gametes of infertile patients is currently unknown, several possibilities have been raised. These include: (a) genetic mutations in the encoding Hspa2 gene, (b) epigenetic regulation of Hspa2 gene expression, and/or (c) perturbations in protein expression/stability arising from exposure of developing germ cells to oxidative stress. With regard to the latter it is possible the oxidative attack could act directly to damage the Hspa2 gene or mRNA transcript. Alternatively, the HSPA2 protein itself may be targeted for destruction following adduction by electrophilic aldehydes generated as a result of reactive oxygen species-induced lipid peroxidation. Such insults are known to lead ubiquitin (Ub)-dependent degradation via proteasomal or lysosomal pathways.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492046&req=5

Figure 2: Mechanisms underpinning the loss of heat shock protein A2 (HSPA2) from the spermatozoa of infertile patients. Although the mechanism(s) underpinning the selective loss of HSPA2 from the differentiating gametes of infertile patients is currently unknown, several possibilities have been raised. These include: (a) genetic mutations in the encoding Hspa2 gene, (b) epigenetic regulation of Hspa2 gene expression, and/or (c) perturbations in protein expression/stability arising from exposure of developing germ cells to oxidative stress. With regard to the latter it is possible the oxidative attack could act directly to damage the Hspa2 gene or mRNA transcript. Alternatively, the HSPA2 protein itself may be targeted for destruction following adduction by electrophilic aldehydes generated as a result of reactive oxygen species-induced lipid peroxidation. Such insults are known to lead ubiquitin (Ub)-dependent degradation via proteasomal or lysosomal pathways.
Mentions: Finally, as an alternative to mRNA damage, it is also possible that the lack of HSPA2 seen in spermatozoa of infertile patients may arise from a mechanism involving the targeted destruction of the protein itself. Consistent with this notion, recent work from our laboratory has shown that electrophilic aldehydes, such as 4-hydroxynonenal (4HNE), generated as a result of reactive oxygen species-induced lipid peroxidation are readily capable of adducting proteins localized within the head of human spermatozoa.89 Furthermore, peptides belonging to HSP70 family members have been identified among the major 4HNE alkylated targets in these damaged cells.89 While the primary impact of 4HNE covalently binding to proteins in mature spermatozoa is likely to involve conformational changes and/or aggregation leading to disruption of their functionality,90 it may have a more pronounced effect in developing germ cells (Figure 2). Indeed in tissues such as the testis, which possess an intrinsic ubiquitin-proteasome system, such insults commonly lead to the activation of a protein degradation cascade that selectively eliminates damaged proteins in an effort to mitigate the impact of oxidative injury.919293 Alternative, ubiquitin-dependent lysosomal degradation mechanisms have also recently been reported for 4HNE-modified proteins.94 Whether such mechanisms underpin the loss of susceptible proteins such as HSPA2 from maturing spermatozoa remains to be established. Similarly, it also has yet to be investigated whether aberrant expression of BAT3 might contribute to this phenotype through accelerated degradation of HSPA254 during human spermatogenesis.

Bottom Line: Although this unique cellular interaction can now be readily by-passed by assisted reproductive strategies such as intracytoplasmic sperm injection (ICSI), recent large-scale epidemiological studies have encouraged the cautious use of this technology and highlighted the need for further research into the mechanisms responsible for defective sperm-egg recognition.While the factors responsible for the regulation of these sequential maturational events are undoubtedly complex, emerging research has identified the molecular chaperone, heat shock protein A2 (HSPA2), as a key regulator of these events in human spermatozoa.HSPA2 is a testis-enriched member of the 70 kDa heat shock protein family that promotes the folding, transport, and assembly of protein complexes and has been positively correlated with in vitro fertilization (IVF) success.

View Article: PubMed Central - PubMed

Affiliation: Priority Research Centre in Reproductive Science; Priority Research Centre in Chemical Biology, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.

ABSTRACT
One of the most common lesions present in the spermatozoa of human infertility patients is an idiopathic failure of sperm-egg recognition. Although this unique cellular interaction can now be readily by-passed by assisted reproductive strategies such as intracytoplasmic sperm injection (ICSI), recent large-scale epidemiological studies have encouraged the cautious use of this technology and highlighted the need for further research into the mechanisms responsible for defective sperm-egg recognition. Previous work in this field has established that the sperm domains responsible for oocyte interaction are formed during spermatogenesis prior to being dynamically modified during epididymal maturation and capacitation in female reproductive tract. While the factors responsible for the regulation of these sequential maturational events are undoubtedly complex, emerging research has identified the molecular chaperone, heat shock protein A2 (HSPA2), as a key regulator of these events in human spermatozoa. HSPA2 is a testis-enriched member of the 70 kDa heat shock protein family that promotes the folding, transport, and assembly of protein complexes and has been positively correlated with in vitro fertilization (IVF) success. Furthermore, reduced expression of HSPA2 from the human sperm proteome leads to an impaired capacity for cumulus matrix dispersal, sperm-egg recognition and fertilization following both IVF and ICSI. In this review, we consider the evidence supporting the role of HSPA2 in sperm function and explore the potential mechanisms by which it is depleted in the spermatozoa of infertile patients. Such information offers novel insights into the molecular mechanisms governing sperm function.

No MeSH data available.


Related in: MedlinePlus