Ubiquitin-activating enzyme E1 inhibitor PYR-41 retards sperm enlargement after fusion to the egg

Keiichi Yoshida; Woojin Kang; Akihiro Nakamura; Natsuko Kawano; Maito Hanai; Mami Miyado; Yoshitaka Miyamoto; Maki Iwai; Toshio Hamatani; Hidekazu Saito; Kenji Miyado; Akihiro Umezawa

doi:10.1016/j.reprotox.2018.01.001

Ubiquitin-activating enzyme E1 inhibitor PYR-41 retards sperm enlargement after fusion to the egg

Reprod Toxicol. 2018 Mar:76:71-77. doi: 10.1016/j.reprotox.2018.01.001. Epub 2018 Feb 3.

Authors

Affiliations

¹ Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan. Electronic address: [email protected].
² Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan; Department of Perinatal Medicine and Maternal Care, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
³ Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan; Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Kanagawa, 214-8571, Japan.
⁴ Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
⁵ Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
⁶ Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
⁷ Department of Perinatal Medicine and Maternal Care, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
⁸ Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan. Electronic address: [email protected].

PMID: 29355596
DOI: 10.1016/j.reprotox.2018.01.001

Abstract

The ubiquitin-proteasome system, which is initiated by a single ubiquitin-activating enzyme E1 (UBE1), is involved in male reproduction via spermatogenesis and function in mammals. Here we explored the influence of UBE1-specific inhibitor, 4[4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (pyrazone-41 or PYR-41) in female reproduction. UBE-1 was detected by immunoblotting and immunocytochemistry in mouse eggs and was localized mainly under the egg plasma membrane. PYR-41 pretreatment suppresses the development of eggs into two-cell embryos. Specifically, pretreatment retarded sperm enlargement and meiotic chromosomal division after sperm-egg fusion. PYR-41 pretreatment disturbed β-catenin, a well-known target protein for ubiquitination, localization under the egg plasma membrane and on spindle microtubules in wild-type eggs. Otherwise, PYR-41 treatment had no effect on the two-cell development of eggs lacking β-catenin. Our results raise the possibility that inhibition of the ubiquitin-proteasome system suppresses sperm enlargement through impaired β-catenin-mediated mechanism.

Keywords: PYR-41; Sperm enlargement; UBE1; Ubiquitin-proteasome system; β-catenin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzoates / toxicity*
Fertilization in Vitro / drug effects*
Furans / toxicity*
Male
Mice, Transgenic
Ovum / drug effects*
Ovum / enzymology
Pyrazoles / toxicity*
Sperm Motility / drug effects
Sperm-Ovum Interactions / drug effects*
Spermatozoa / drug effects*
Ubiquitin-Activating Enzymes / antagonists & inhibitors*
Ubiquitination / drug effects
beta Catenin / genetics

Substances

4(4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl)-benzoic acid ethyl ester
Benzoates
Furans
Pyrazoles
beta Catenin
Ubiquitin-Activating Enzymes