A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells
Oxidative stress is a leading causative agent in the defective sperm function associated with male infertility. Such stress commonly manifests via the accumulation of pathological levels of the electrophilic aldehyde, 4-hydroxynonenal (4HNE), generated as a result of lipid peroxidation. This highly...
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Format: | Article |
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Frontiers Media S.A.
2019-12-01
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Series: | Frontiers in Cell and Developmental Biology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2019.00319/full |
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doaj-7ecc4bb88d25498fa20ae3cf1122467c |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Brett Nixon Brett Nixon Ilana R. Bernstein Ilana R. Bernstein Shenae L. Cafe Shenae L. Cafe Maryse Delehedde Nicolas Sergeant Nicolas Sergeant Amanda L. Anderson Amanda L. Anderson Natalie A. Trigg Natalie A. Trigg Andrew L. Eamens Andrew L. Eamens Tessa Lord Tessa Lord Matthew D. Dun Matthew D. Dun Geoffry N. De Iuliis Geoffry N. De Iuliis Elizabeth G. Bromfield Elizabeth G. Bromfield Elizabeth G. Bromfield |
spellingShingle |
Brett Nixon Brett Nixon Ilana R. Bernstein Ilana R. Bernstein Shenae L. Cafe Shenae L. Cafe Maryse Delehedde Nicolas Sergeant Nicolas Sergeant Amanda L. Anderson Amanda L. Anderson Natalie A. Trigg Natalie A. Trigg Andrew L. Eamens Andrew L. Eamens Tessa Lord Tessa Lord Matthew D. Dun Matthew D. Dun Geoffry N. De Iuliis Geoffry N. De Iuliis Elizabeth G. Bromfield Elizabeth G. Bromfield Elizabeth G. Bromfield A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells Frontiers in Cell and Developmental Biology 4-hydroxynonenal A-kinase anchor protein 4 male germ cells oxidative stress spermatozoa sperm capacitation |
author_facet |
Brett Nixon Brett Nixon Ilana R. Bernstein Ilana R. Bernstein Shenae L. Cafe Shenae L. Cafe Maryse Delehedde Nicolas Sergeant Nicolas Sergeant Amanda L. Anderson Amanda L. Anderson Natalie A. Trigg Natalie A. Trigg Andrew L. Eamens Andrew L. Eamens Tessa Lord Tessa Lord Matthew D. Dun Matthew D. Dun Geoffry N. De Iuliis Geoffry N. De Iuliis Elizabeth G. Bromfield Elizabeth G. Bromfield Elizabeth G. Bromfield |
author_sort |
Brett Nixon |
title |
A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells |
title_short |
A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells |
title_full |
A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells |
title_fullStr |
A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells |
title_full_unstemmed |
A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells |
title_sort |
kinase anchor protein 4 is vulnerable to oxidative adduction in male germ cells |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2019-12-01 |
description |
Oxidative stress is a leading causative agent in the defective sperm function associated with male infertility. Such stress commonly manifests via the accumulation of pathological levels of the electrophilic aldehyde, 4-hydroxynonenal (4HNE), generated as a result of lipid peroxidation. This highly reactive lipid aldehyde elicits a spectrum of cytotoxic lesions owing to its propensity to form stable adducts with biomolecules. Notably however, not all elements of the sperm proteome appear to display an equivalent vulnerability to 4HNE modification, with only a small number of putative targets having been identified to date. Here, we validate one such target of 4HNE adduction, A-Kinase Anchor Protein 4 (AKAP4); a major component of the sperm fibrous sheath responsible for regulating the signal transduction and metabolic pathways that support sperm motility and capacitation. Our data confirm that both the precursor (proAKAP4), and mature form of AKAP4, are conserved targets of 4HNE adduction in primary cultures of post-meiotic male germ cells (round spermatids) and in mature mouse and human spermatozoa. We further demonstrate that 4HNE treatment of round spermatids and mature spermatozoa results in a substantial reduction in the levels of both proAKAP4 and AKAP4 proteins. This response proved refractory to pharmacological inhibition of proteolysis, but coincided with an apparent increase in the degree of protein aggregation. Further, we demonstrate that 4HNE-mediated protein degradation and/or aggregation culminates in reduced levels of capacitation-associated phosphorylation in mature human spermatozoa, possibly due to dysregulation of the signaling framework assembled around the AKAP4 scaffold. Together, these findings suggest that AKAP4 plays an important role in the pathophysiological responses to 4HNE, thus strengthening the importance of AKAP4 as a biomarker of sperm quality, and providing the impetus for the design of an efficacious antioxidant-based intervention strategy to alleviate sperm dysfunction. |
topic |
4-hydroxynonenal A-kinase anchor protein 4 male germ cells oxidative stress spermatozoa sperm capacitation |
url |
https://www.frontiersin.org/article/10.3389/fcell.2019.00319/full |
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doaj-7ecc4bb88d25498fa20ae3cf1122467c2020-11-25T02:16:37ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2019-12-01710.3389/fcell.2019.00319484392A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ CellsBrett Nixon0Brett Nixon1Ilana R. Bernstein2Ilana R. Bernstein3Shenae L. Cafe4Shenae L. Cafe5Maryse Delehedde6Nicolas Sergeant7Nicolas Sergeant8Amanda L. Anderson9Amanda L. Anderson10Natalie A. Trigg11Natalie A. Trigg12Andrew L. Eamens13Andrew L. Eamens14Tessa Lord15Tessa Lord16Matthew D. Dun17Matthew D. Dun18Geoffry N. De Iuliis19Geoffry N. De Iuliis20Elizabeth G. Bromfield21Elizabeth G. Bromfield22Elizabeth G. Bromfield23Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW, AustraliaPregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, AustraliaPriority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW, AustraliaPregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, AustraliaPriority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW, AustraliaPregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, AustraliaSPQI – 4BioDx-Breeding Section, Lille, FranceSPQI – 4BioDx-Breeding Section, Lille, FranceUniversity of Lille, INSERM UMRS, Lille, FrancePriority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW, AustraliaPregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, AustraliaPriority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW, AustraliaPregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, AustraliaPriority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW, AustraliaPregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, AustraliaPriority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW, AustraliaPregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, AustraliaCancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, AustraliaPriority Research Centre for Cancer Research Innovation and Translation, Hunter Medical Research Institute, New Lambton Heights, NSW, AustraliaPriority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW, AustraliaPregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, AustraliaPriority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, Callaghan, NSW, AustraliaPregnancy and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, AustraliaDepartment of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, NetherlandsOxidative stress is a leading causative agent in the defective sperm function associated with male infertility. Such stress commonly manifests via the accumulation of pathological levels of the electrophilic aldehyde, 4-hydroxynonenal (4HNE), generated as a result of lipid peroxidation. This highly reactive lipid aldehyde elicits a spectrum of cytotoxic lesions owing to its propensity to form stable adducts with biomolecules. Notably however, not all elements of the sperm proteome appear to display an equivalent vulnerability to 4HNE modification, with only a small number of putative targets having been identified to date. Here, we validate one such target of 4HNE adduction, A-Kinase Anchor Protein 4 (AKAP4); a major component of the sperm fibrous sheath responsible for regulating the signal transduction and metabolic pathways that support sperm motility and capacitation. Our data confirm that both the precursor (proAKAP4), and mature form of AKAP4, are conserved targets of 4HNE adduction in primary cultures of post-meiotic male germ cells (round spermatids) and in mature mouse and human spermatozoa. We further demonstrate that 4HNE treatment of round spermatids and mature spermatozoa results in a substantial reduction in the levels of both proAKAP4 and AKAP4 proteins. This response proved refractory to pharmacological inhibition of proteolysis, but coincided with an apparent increase in the degree of protein aggregation. Further, we demonstrate that 4HNE-mediated protein degradation and/or aggregation culminates in reduced levels of capacitation-associated phosphorylation in mature human spermatozoa, possibly due to dysregulation of the signaling framework assembled around the AKAP4 scaffold. Together, these findings suggest that AKAP4 plays an important role in the pathophysiological responses to 4HNE, thus strengthening the importance of AKAP4 as a biomarker of sperm quality, and providing the impetus for the design of an efficacious antioxidant-based intervention strategy to alleviate sperm dysfunction.https://www.frontiersin.org/article/10.3389/fcell.2019.00319/full4-hydroxynonenalA-kinase anchor protein 4male germ cellsoxidative stressspermatozoasperm capacitation |