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Mouse Zygote-Specific Proteasome Assembly Chaperone Important for Maternal-To-Zygotic Transition

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Mouse Zygote-Specific Proteasome Assembly Chaperone Important for Maternal-To-Zygotic Transition 170 Research Article Mouse zygote-specific proteasome assembly chaperone important for maternal-to-zygotic transition Seung-Wook Shin1,2, Natsumi Shimizu1, Mikiko Tokoro1,3, Satoshi Nishikawa1, Yuki Hatanaka1, Masayuki Anzai4, Jun Hamazaki2, Satoshi Kishigami1, Kazuhiro Saeki1, Yoshihiko Hosoi1, Akira Iritani1, Shigeo Murata2 and Kazuya Matsumoto1,* 1Division of Biological Science, Graduate School of Biology-Oriented Science and Technology, Kinki University, 930 Nishimitani, Kinokawa, Wakayama 649-6493, Japan 2Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113- 0033, Japan 3Laboratory for Genomic Reprogramming Center for Developmental Biology, RIKEN Kobe Institute, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan 4Institute of Advanced Technology, Kinki University, 14-1 Minamiakasaka, Kainan, Wakayama 642-0017, Japan *Author for correspondence ([email protected]) Biology Open 2, 170–182 doi: 10.1242/bio.20123020 Received 1st September 2012 Accepted 18th October 2012 Summary During the maternal-to-zygotic transition (MZT), maternal ZPAC in early embryos caused a significant reduction of proteins in oocytes are degraded by the ubiquitin–proteasome proteasome activity and decrease in Ump1 and mature system (UPS), and new proteins are synthesized from the proteasomes, leading to accumulation of proteins that need zygotic genome. However, the specific mechanisms to be degraded at the MZT and early developmental arrest. underlying the UPS at the MZT are not well understood. Therefore, a unique proteasome assembly pathway mediated We identified a molecule named zygote-specific proteasome by ZPAC is important for progression of the mouse MZT. assembly chaperone (ZPAC) that is specifically expressed in mouse gonads, and expression of ZPAC was transiently ß 2012. Published by The Company of Biologists Ltd. This is increased at the mouse MZT. ZPAC formed a complex with an Open Access article distributed under the terms of the Ump1 and associated with precursor forms of 20S Creative Commons Attribution Non-Commercial Share Alike Biology Open proteasomes. Transcription of ZPAC genes was also under License (http://creativecommons.org/licenses/by-nc-sa/3.0). the control of an autoregulatory feedback mechanism for the compensation of reduced proteasome activity similar to Ump1 Key words: ZPAC, Maternal-to-zygotic transition, Ubiquitin– and 20S proteasome subunit gene expression. Knockdown of proteasome system Introduction Another proteolytic pathway is the ubiquitin–proteasome After fertilization, erasure of the oogenic program and reprogramming mediated degradation. Unlike autophagy, protein degradation by by establishing the embryonic program into totipotent zygotes are UPS occurs in a selective manner, which is owed to ubiquitin ligases coordinately regulated (Pellettieri et al., 2003; DeRenzo and Seydoux, that specifically recognize substrate proteins and attach 2004; Stitzel and Seydoux, 2007). This process is called maternal-to- polyubiquitin chains to them as a degradation signal for the zygotic transition (MZT) and is accompanied by degradation of proteasome (Coux et al., 1996; Baumeister et al., 1998). The UPS is maternal mRNAs and proteins and transcription of zygotic genes essential for maintenance of cellular homeostasis in eukaryotic cells (Keshet et al., 1988; Evsikov and Marı´n de Evsikova, 2009; Shin et (Varshavsky, 2005; Ciechanover, 2006; Tai and Schuman, 2008). al., 2010). Oocyte-derived mRNAs are degraded shortly after The proteasome is a highly conserved protein degradation fertilization, and ,90% of RNAs stored in the oocyte are degraded machine made up of two complexes: the catalytic 20S proteasome by the 2-cell stage, which is an essential process for embryogenesis (also called core particle) and the 19S regulatory particle (RP), (Stitzel and Seydoux, 2007). Degradation of maternal proteins is also both of which are composed of a set of multiple distinct subunits suggested to be an essential component of the MZT (Mendez et al., (Coux et al., 1996; Schmidt et al., 2005). The 20S proteasome is 2002; DeRenzo and Seydoux, 2004; Huo et al., 2004). composed of 28 subunits arranged in a cylindrical particle as four Two major pathways for bulk degradation of intracellular heteroheptameric rings, a1–7b1–7b1–7a1–7 (Baumeister et al., 1998; proteins exist in eukaryotic cells, one of which is the autophagy- Maupin-Furlow et al., 2006), the correct assembly of which mediated lysosomal degradation. Recently, the importance of requires a set of dedicated chaperones named proteasome autophagy for preimplantation development has been highlighted assembly chaperone (PAC) 1–4 (Psmg1–4) and ubiquitin- in studies using mice (Tsukamoto et al., 2008). They reported that mediated proteolysis 1 (Ump1, also called POMP or oocyte-specific Atg5-knockout mice exhibited early embryonic Proteassemblin) (Ramos et al., 1998; Ellis, 2006; Fricke et al., arrest at the 4-cell or 8-cell stage, indicating that autophagy is 2007; Kusmierczyk and Hochstrasser, 2008; Ramos and Dohmen, important for the overt morphological changes in these stages. 2008; Rosenzweig and Glickman, 2008; Murata et al., 2009). Proteasome in the MZT 171 Involvement of the UPS in the degradation of stored maternal signals for Ump1 proteins were also detected in spermatogonia and proteins after fertilization has already been reported (Evsikov et oocytes using immunohistochemical staining, similar to ZPAC al., 2004; Solter et al., 2004), and in general, degradation by the protein (Fig. 1E), showing that both ZPAC and Ump1 are highly UPS is carefully regulated. However, the mechanisms underlying expressed in the germ cells. the structure and functions of the UPS at the maternal-to-zygotic Since ZPAC is specifically expressed in mouse gonads and transition are not well understood. Ump1 is ubiquitously expressed in mouse tissues, we examined In this study, we identified a molecule that we named zygote- whether ZPAC and Ump1 interact with each other in mouse specific proteasome assembly chaperone (ZPAC), which is gonads. Proteins extracted from testes and ovaries were subjected specifically expressed in the mouse gonads and zygote. In the to immunoprecipitation using anti-ZPAC antibody. This showed early mouse embryo, expression of ZPAC is transiently augmented that ZPAC and Ump1 formed a complex in these cells (Fig. 1F). at the MZT and plays an important role in the removal of maternal The association of ZPAC with the proteasome assembly proteins by enhancing the biogenesis of the 20S proteasome. chaperone Ump1 led us to examine the possibility of whether a mouse gonad-specific protein ZPAC collaborates with Ump1 in Results the ubiquitin–proteasome system. Identification of ZPAC as an Ump1 interacting protein To understand the mechanism governing entry of oocytes to Unique expression of ZPAC during the MZT totipotent zygotes during the MZT of early mouse embryos, we Since ZPAC was expressed specifically in germ cells including identified genes whose expression was specifically changed at the oocytes, we examined gene expression profiles and subcellular MZT using an mRNA differential display analysis comparing localization of ZPAC as well as Ump1 during early mouse embryos at the late 1-cell stage with oocytes at the MII stage embryogenesis. In early mouse embryos, the ZPAC gene showed (supplementary material Fig. S1A). Of the genes identified, one a unique expression profile, in which the level of ZPAC mRNA was a gene that we named ZPAC (supplementary material Fig. and protein transiently increased at the early 2-cell stage and then S1B). Mouse ZPAC localized in chromosome 14 A3, which has 7 drastically decreased by the late 2-cell and 8-cell stages exons (supplementary material Fig. S1C,D). DNA sequences of (Fig. 2A), indicating that the identification of ZPAC in the ZPAC showed an open reading frame of 1056 base pairs encoding differential display screen does not fully reflect the true behavior a 351 amino acid protein with a predicted molecular mass of of this transcript. The amount of Ump1 mRNA was highest in 41.5 kDa (supplementary material Fig. S1E,F). The official oocytes and began to decrease as early as the 1-cell stage. symbol of the ZPAC gene is E330034G19Rik (GeneBank However, the abundance of Ump1 protein was maintained from AAI39084), which was not functionally characterized but was the 1-cell stage to the 4-cell stage, even after its mRNA level was predicted to be preferentially expressed in mouse oocytes and markedly decreased, and it appears that the levels of ZPAC and early embryos according to its EST profile described in the Ump1 proteins were coordinately regulated (Fig. 2A). We UniGene database. calculated the ratio of ZPAC/Ump1 proteins at the early Biology Open To elucidate the function of ZPAC, we performed a yeast two- embryonic developmental stage (supplementary material Fig. hybrid screen of a mouse ovary cDNA library using ZPAC as a S6). This analysis showed a nearly constant ratio of ZPAC/Ump1 bait and identified Ump1 as a protein interacting with ZPAC protein during early zygote development, suggesting that ZPAC (supplementary material Fig. S2). Ump1 is known as an assembly may form a stoichiometric complex with Ump1. chaperone that facilitates the formation of 20S proteasomes and Consistent with the immunoblot analysis, intense signals of is especially required for the initiation of b-ring formation. Ump1 both ZPAC and Ump1 proteins were diffusely
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