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Lack of androgen receptor SUMOylation results in male infertility due to epididymal dysfunction.

ABSTRACT: Androgen receptor (AR) is regulated by SUMOylation at its transactivation domain. In vitro, the SUMOylation is linked to transcriptional repression and/or target gene-selective regulation. Here, we generated a mouse model (ArKI) in which the conserved SUMO acceptor lysines of AR are permanently abolished (ArK381R, K500R). ArKI males develop normally, without apparent defects in their systemic androgen action in reproductive tissues. However, the ArKI males are infertile. Their spermatogenesis appears unaffected, but their epididymal sperm maturation is defective, shown by severely compromised motility and fertilization capacity of the sperm. Fittingly, their epididymal AR chromatin-binding and gene expression associated with sperm maturation and function are misregulated. AR is SUMOylated in the wild-type epididymis but not in the testis, which could explain the tissue-specific response to the lack of AR SUMOylation. Our studies thus indicate that epididymal AR SUMOylation is essential for the post-testicular sperm maturation and normal reproductive capability of male mice.

SUBMITTER: Zhang FP

PROVIDER: S-EPMC6377611 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Lack of androgen receptor SUMOylation results in male infertility due to epididymal dysfunction.

Zhang Fu-Ping FP Malinen Marjo M Mehmood Arfa A Lehtiniemi Tiina T Jääskeläinen Tiina T Niskanen Einari A EA Korhonen Hanna H Laiho Asta A Elo Laura L LL Ohlsson Claes C Kotaja Noora N Poutanen Matti M Sipilä Petra P Palvimo Jorma J JJ

Nature communications 20190215 1

Androgen receptor (AR) is regulated by SUMOylation at its transactivation domain. In vitro, the SUMOylation is linked to transcriptional repression and/or target gene-selective regulation. Here, we generated a mouse model (ArKI) in which the conserved SUMO acceptor lysines of AR are permanently abolished (Ar<sup>K381R, K500R</sup>). ArKI males develop normally, without apparent defects in their systemic androgen action in reproductive tissues. However, the ArKI males are infertile. Their spermat ...[more]

PMID: 30770815

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Project description:Occludin (OCLN) is a tight junction protein and Ocln deletion mutation causes male infertility in mice. However, the role of OCLN in male reproductive system remains unknown. In this study, we used an interdisciplinary approach to elucidate the underlying mechanism of male infertility in related to OCLN function, including Ocln knockout mice as well as a combined omics analysis and immunofluorescent labelling. Our results showed that the epididymis of Ocln-null mice displayed a phenomenon resembling epididymal sperm granuloma, which occurred especially in the junctional region between caput and corpus epididymidis. Sperm motility and fertilisation capacity were also impaired in these Ocln-null mice, accompanied by enlarged tubules in the proximal regions and degeneration in the distal regions of epididymis. Cellular localization analysis showed that OCLN immunofluorescence was enriched only in the apical junction of epithelial principal cells in the proximal regions of epididymis. Integrative omics analysis revealed the downregulation of gene clusters enriched in acid secretion and fatty acid metabolism in the Ocln-null epididymis, especially the enzymes related to the unsaturated arachidonic acid pathway. The number of proton-pump V-ATPase-expression clear cells, a key player of luminal acidification in the epididymis, declined drastically from prepubertal age before sperm arrival but not in the early postnatal age. This was accompanied by programmed cell death of clear cells and increased pH in the epididymal fluid of OCLN-deficient mice. The lipidomics results showed significantly increased levels of specific DAGs conjugated to unsaturated fatty acids in the Ocln-mutant. Immunofluorescent labelling showed that the arachidonic acid converting enzyme PTGDS and phospholipase PLA2g12a were prominently altered in the principal cells and luminal contents of the Ocln-mutant epididymis. Whereas the carboxylate ester lipase CES1, originally enriched in the WT basal cells, was found upregulated in the Ocln-mutant principal cells. Overall, this study demonstrates that OCLN is essential for maintaining caput-to-corpus epithelial integrity, survival of acid-secreting clear cells, and unsaturated fatty acid catabolism in the mouse epididymis, thereby ensuring sperm maturation and male fertility.

Project description:BackgroundEpididymal tuberculosis (TB) is an uncommon form of TB, although it is known to develop frequently in the male reproductive system. Infertility is rare but important among subsequent possible complications caused by the disease, particularly in young males. Moreover, it is difficult to differentiate epididymal TB from other epididymo-testicular diseases. Herein, we report a rare case of a young patient recently diagnosed with bilateral epididymal TB causing male infertility.Case descriptionWe report the case of a 37-year-old patient who presented with left testicular pain and swelling lasting for about 8 months. He had no comorbidities, including pulmonary TB. Additionally, he had no children and was worried about infertility. Physical examination revealed a firm and tender mass, which was palpable in the left epididymal area, measuring 3.5 cm × 2.2 cm in diameter. Acid-fast bacilli staining and polymerase chain reaction of the urine were negative. Semen analysis showed no sperm in the semen, implying azoospermia diagnosis. Scrotal ultrasonography was suggestive of severe left epididymitis with abscess formation without abnormal appearance of the testicle. Due to persistent testicular pain, intermittent fever, and severe epididymitis with abscess formation, the patient underwent epididymectomy. Surgical exploration of the testicle revealed a severely swollen and firm epididymis with abscess materials and hard and dilated vas deferens connected to the epididymis, implying severe inflammatory reactions. The histopathological examination revealed chronic granulomatous inflammation with caseous necrosis in the epididymis tissue. According to histopathological results, the patient was treated with anti-TB pharmacological treatment. About 1 month after the surgery, he presented with pain in the right testicular area, implying bilateral TB epididymis. After completion of the pharmacological treatment, the patient had no complaints, such as pain or swelling in both testicular areas.ConclusionsPhysicians should consider the possibility of epididymal TB in patients with persistent testicular symptoms for early diagnosis. When a definitive diagnosis of epididymal TB is established, or clinically suspected, immediate treatment initiation, including pharmacological and, if needed, surgical treatment, should be performed to prevent subsequent complications, including abscess formation or male infertility, particularly in young males.

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Lack of androgen receptor SUMOylation results in male infertility due to epididymal dysfunction.

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Lack of androgen receptor SUMOylation results in male infertility due to epididymal dysfunction.

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