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Construction and analysis of the testis/sperm-enriched interaction network: identification of potential PPP1CC2 complexes as targets for male contraception

ABSTRACT: Phosphoprotein phosphatase 1 catalytic subunit gamma 2 (PPP1CC2), a PPP1 isoform restricted to testicular germ cells and spermatozoa, is essential for completion of spermatogenesis and highly similar PPP1C isoforms are capable of compensating for the loss of Ppp1cc in every tissue except in testis. In addition, inhibition of the enzymatic activity of PPP1C in spermatozoa stimulates motility. The key to understand the regulation of PPP1CC2 lies in the identification and characterization of its interacting partners. By integrating tissue-specific protein expression and protein-protein interaction data, we identified testis/sperm-enriched/specific PPP1CC complexes and potential key PPP1 interacting proteins (PIPs) for male reproduction. We constructed a testis/sperm-enriched network, analyzed several topological properties and specified the biological/physiological properties of the proteins in the network. Proteins were classified into modules according to their topological features and functional annotations, which clarified the mechanisms underlying testis and sperm function and, more specifically, the role of PPP1CC in spermatogenesis and sperm motility. Previously uncharacterized PIPs, such as AKAP4, were identified based on analyses of the interaction network. The PPP1CC2 interaction with AKAP4 in human sperm was also validated by different methods and the complex was proposed as potential targets for male contraception due to its significance in spermatozoa motility.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Testis, Sperm

SUBMITTER: Pieter-Jan De Bock

LAB HEAD: Kris Gevaert

PROVIDER: PXD002888 | Pride | 2022-02-28

REPOSITORIES: Pride

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			Action	DRS
	30b377965d64e7ae___R20527_IP.RAW.-1.mgf	Mgf
	30b377965d64e7ae___R20527_IP.RAW.-1.pride.mgf.gz	Mgf
	30b377965d64e7ae___R20529_pre-clearance.RAW.-1.mgf	Mgf
	30b377965d64e7ae___R20529_pre-clearance.RAW.-1.pride.mgf.gz	Mgf
	F082750.mzid.gz	Mzid

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Project description:The specific role of polyamines in the testis physiology is not fully understood. Antizymes (OAZs) and antizyme inhibitors (AZINs) are modulators of ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis and polyamine uptake. Although the three known OAZs are expressed in the testis, only OAZ3 is testis specific and has been proven to have an essential role in male fertility. Regarding the two existing AZINs, AZIN2 is the most abundantly expressed member in this gonad. Whereas previous studies suggested that AZIN2 might participate in mouse spermatogenesis, immunohistological analysis of human testicular sections revealed that AZIN2 is also detected in the steroidogenic Leydig cells but not in the germinal epithelium. In the present study, we found a close ontogenic similarity in the mRNA levels of OAZs and AZINs between mice and rats, but an opposite expression pattern of ODC activity. Further analysis of AZIN2 and OAZ3 in the testis of mice with different alterations in spermatogenesis and fertility, induced either genetically or pharmacologically, corroborated that both AZIN2 and OAZ3 are mainly expressed in the haploid germinal cells. Finally, by using transgenic mice with a truncated Azin2 gene fused to the bacterial lacZ gene, we studied the expression of Azin2 in testes, epididymides and spermatozoa. AZIN2 was detected in spermatids and spermatozoa, as well as in Leydig cells, and in epithelial epidydimal cells. Azin2 knock-out male mice were fertile; however, they showed marked decreases in testicular putrescine and plasma and testicular testosterone levels, and a dramatic reduction in the sperm motility. These results suggest an important role for AZIN2 in testicular cells by modulating polyamine concentrations, testosterone synthesis and sperm function. Overall, our data corroborate the relevance of polyamine regulation in spermatogenesis, where both AZIN2 and OAZ3 play fundamental roles. We used microarrays in order to detect how the disruption of Azin2 could affect overall gene expression in testis.

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Construction and analysis of the testis/sperm-enriched interaction network: identification of potential PPP1CC2 complexes as targets for male contraception

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