A‐kinase anchor protein 4 precursor (pro‐AKAP4) in human spermatozoa

Jumeau, Fanny; Sigala, Julien; Dossou-Gbete, F.; Frimat, K.; Barbotin, Anne Laure; Buée, Luc; Behal, Hélène; Sergeant, Nicolas; Mitchell, Valérie

doi:10.1111/andr.12524

Cited by 36 publications

(35 citation statements)

References 19 publications

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“…By contrast, and in agreement with our own data, proAKAP4 is retained within the flagellum of mature human spermatozoa, where it co-localizes with AKAP4 throughout the fibrous sheath (Turner et al, 1998;Jumeau et al, 2018). Notably however, striking differences in proAKAP4 abundance have been documented in the semen of normozoospermic individuals, wherein the quantity of the protein is positively correlated with sperm motility; albeit in the high-quality cells recovered by density gradient centrifugation (Jumeau et al, 2018). Whilst these data invite speculation that the extent of proAKAP4 processing may reflect the integrity of post-testicular sperm maturation, and hence contribute to differences in the motility profile of human spermatozoa, there is currently no causal evidence to substantiate such an association.…”

Section: Discussionsupporting

confidence: 92%

“…proAKAP4 has been reported to localize along the entire length of the principal piece of mouse testicular spermatozoa before becoming restricted to the proximal portion of the flagellum in mature cauda epididymal spermatozoa (Johnson et al, 1997); suggestive of an additional wave of proAKAP4 processing during epididymal sperm maturation. By contrast, and in agreement with our own data, proAKAP4 is retained within the flagellum of mature human spermatozoa, where it co-localizes with AKAP4 throughout the fibrous sheath (Turner et al, 1998;Jumeau et al, 2018). Notably however, striking differences in proAKAP4 abundance have been documented in the semen of normozoospermic individuals, wherein the quantity of the protein is positively correlated with sperm motility; albeit in the high-quality cells recovered by density gradient centrifugation (Jumeau et al, 2018).…”

Section: Discussionsupporting

confidence: 90%

“…Whilst these data invite speculation that the extent of proAKAP4 processing may reflect the integrity of post-testicular sperm maturation, and hence contribute to differences in the motility profile of human spermatozoa, there is currently no causal evidence to substantiate such an association. Rather, it has been postulated that proAKAP4 may serve as a "reservoir" that can be activated to generate mature AKAP4 and thus rescue sperm motility, if and when required (Jumeau et al, 2018;Sergeant et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, these cross species analyses identify the potential use of proAKAP4 and AKAP4 as diagnostic biomarkers of overall semen quality (Sergeant et al, 2019). At present however, it remains uncertain what factor(s) contribute to the striking differences in proAKAP4 and AKAP4 levels documented in livestock (Blommaert et al, 2019) and human spermatozoa (Jumeau et al, 2018). Here, we sought to validate proAKAP4 and AKAP4 as targets for chemical alkylation by 4HNE, and to explore the consequences of 4HNE-mediated alkylation of proAKAP4 and AKAP4 during key phases of sperm development.…”

Section: Introductionmentioning

confidence: 99%

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A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

Nixon

Bernstein

Cafe

et al. 2019

Front. Cell Dev. Biol.

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

Nixon

Bernstein

Cafe

et al. 2019

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Previous investigation identified that AKAP4 is a member of the AKAP family, which constitutes a conserved family of signal‐organising scaffolding proteins involved in a series of cellular processes, especially in human spermatogenesis (Jumeau et al., 2018; Luconi et al., 2011). A genome‐wide survey identified AKAP4 as the testis‐restricted cancer‐testis antigen (CTA) (Hofmann et al., 2008).…”

Section: Discussionmentioning

confidence: 99%

Identification of new biomarkers in immune microenvironment of testicular germ cell tumour

Song

Kang

et al. 2021

Andrologia

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To seek novel prognostic biomarkers for testicular germ cell tumour (TGCT) and investigate the tumour immune microenvironment, we identified critical differentially expressed genes (DEGs) by overlapping GSE1818 dataset from Gene Expression Omnibus (GEO). Protein–protein interaction (PPI) network was used to investigate key modules and hub genes. Functional enrichment analysis was performed to investigate the underlying molecular functions of the DEGs in TGCT development and progression. The following survival analysis based on The Cancer Genome Atlas (TCGA) TGCT dataset indicated that AKAP4, SPA17 and TNP1 are correlated with TGCT prognosis. Immunohistochemistry and quantitative real‐time polymerase chain reaction verified the down‐regulation of the 3 hub genes in TGCT. Gene set enrichment analysis was conducted to further explore the role of the 3 hub genes in TGCT respectively. In addition, TGCT samples had high infiltration of CD8+ T cells, M0 and M1 macrophage cells, and resting myeloid dendritic cells in immune microenvironment. We also constructed the microRNA‐gene regulatory networks to identify the key upstream microRNAs in TGCT. In conclusion, our findings indicated that AKAP4, SPA17 and TNP1 are promising biomarkers of TGCT. AKAP4 and TNP1 might regulate immune cells infiltration in immune microenvironment.

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A new hemizygous missense mutation, c.454T＞C (p.S152P), in AKAP4 gene is associated with asthenozoospermia

Liu

Yang

et al. 2021

Molecular Reproduction Devel

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Asthenozoospermia (ASZ) is a condition characterized by reduced forward motility of spermatozoa affecting approximately 19% of infertile men. A kinase anchor protein 4 (AKAP4) is an X‐linked testis‐specific gene and plays a major role in sperm motility and flagella formation. However, few studies have reported its association with ASZ. Here, we sequenced for exonic mutations of human AKAP4 gene by high‐fidelity PCR/Sanger sequencing in peripheral blood samples from 150 ASZ patients and 150 fertile men. We reported the identification of three novel hemizygous mutations unique to four ASZ patients, including one patient carrying missense mutation c.454T>C (p.S152P), two patient carrying synonymous mutation c.1173T>C (p.H391H), and one patient carrying synonymous mutation c.2007 A>G (p.R669R). The p.S152P mutation was located in a precursor pro‐polypeptide domain of AKAP4 protein, which was predicted to be damaging by SIFT and PolyPhen‐2 and could cause the protein accumulation in the cytoplasm of COS‐7 cells. The mature protein of AKAP4 was absent in spermatozoa of ASZ patient harboring AKAP4 p.S152P mutation. Further in vitro cellular assays showed that reactive oxygen species (ROS), malondialdehyde (MDA), myeloperoxidase (MPO) levels, and apoptotic cells were increased in GC2‐spd cells by AKAP4 p.S152P mutant protein, whereas superoxide dismutase (SOD) level was decreased. AKAP4 p.H391H and p.R669R mutant proteins were coimmunoprecipitated with ribonuclease T2 (RNASET2) protein in GC2‐spd cells, whereas no interaction between the AKAP4 p.S152P mutant protein and RNASET2 protein was observed. In addition, AKAP4 p.S152P mutant protein could decrease the activity of PKA/PI3K signaling. Overall, our study identifies a novel AKAP4 p.S152P mutation is associated with ASZ probably through affecting oxidative stress and cell apoptosis by regulating the interaction with RNASET2 and the activity of the PKA/PI3K signaling pathway.

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A‐kinase anchor protein 4 precursor (pro‐AKAP4) in human spermatozoa

Abstract: This study generated new knowledge about pro-AKAP4 in human semen, which may be of interest in the management of male infertility.

Cited by 36 publications

References 19 publications

A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

Identification of new biomarkers in immune microenvironment of testicular germ cell tumour

A new hemizygous missense mutation, c.454T＞C (p.S152P), in AKAP4 gene is associated with asthenozoospermia

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