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Ubiquitin–Proteasome System and Small Protein Modifiers in Gametogenesis and Fertility

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Reproductive Cells and Development".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 20279

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Special Issue Editors

Dr. Peter Sutovsky

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Guest Editor

College of Agriculture, Food & Natural Resources, University of Missouri, Columbia, MI, USA
Interests: sperm function; fertilization; male infertility

Dr. Michal Zigo

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Co-Guest Editor

College of Agriculture, Food & Natural Resources, University of Missouri, Columbia, MI, USA
Interests: sperm physiology and fertilization

Special Issue Information

Dear Colleagues,

We cordially invite you, the experts in the field, to submit your valuable research to the Special Issue “Ubiquitin–Proteasome System and Small Protein Modifiers in Gametogenesis and Fertility” for the Cells journal either in the form of a short communication, original research paper, or review article that will enhance our understanding of protein modification and degradation pathways and their components as they relate to gamete production, quality control, and function during fertilization and preimplantation embryo development.

A small-protein posttranslational modification of proteins by small modifiers such as ubiquitin, SUMO, ISG, and NEDD is required for the correct development of both female and male gametes. The most studied pathway, the ubiquitin–proteasome system, participates in the biological processes of gametes, including mitochondrial inheritance/sperm mitophagy after fertilization; the ubiquitin-dependent mechanisms for meiotic and post-meiotic germ cell quality control; testicular spermatid differentiation; oocyte maturation; sperm capacitation; sperm–ZP penetration (sperm proteasome as the egg coat lysine); as well as pronuclear development after fertilization. Similarly, SUMOylation has been implicated in both oogenesis and spermatogenesis; examples include germinal vesicle breakdown, meiotic spindle formation and sustenance, polar body extrusion, and chromosome segregation during oogenesis. In spermatogenesis, examples include the condensation of chromosomes, meiotic sex chromosome inactivation, microtubule-based structure assembly, and spermatid elongation. Despite the considerable progress that has been made to understand these pathways and their components, additional efforts are necessary to grasp the complexity of the gametic protein modifiers in their entirety.

Dr. Peter Sutovsky
Guest Editors
Dr. Michal Zigo
Co-Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ubiquitin–proteasome system
small ubiquitin-like modifiers
SUMO
ISG15
ISGylation
NEDD4
neddylation
gametogenesis
spermatogenesis
oogenesis, fertilization
zygote
embryo

Published Papers (6 papers)

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Research

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14 pages, 2768 KiB

Open AccessArticle

Protein Kinase A (PRKA) Activity Is Regulated by the Proteasome at the Onset of Human Sperm Capacitation

by Héctor Zapata-Carmona, Lina Barón, Milene Kong and Patricio Morales

Cells 2021, 10(12), 3501; https://doi.org/10.3390/cells10123501 - 11 Dec 2021

Cited by 7 | Viewed by 2460

Abstract

The proteasome increases its activity at the onset of sperm capacitation due to the action of the SACY/PRKACA pathway; this increase is required for capacitation to progress. PRKA activity also increases and remains high during capacitation. However, intracellular levels of cAMP decrease in this process. Our goal was to evaluate the role of the proteasome in regulating PRKA activity once capacitation has started. Viable human sperm were incubated in the presence and absence of epoxomicin or with 0.1% DMSO. The activity of PRKA; the phosphorylation pattern of PRKA substrates (pPRKAs); and the expression of PRKAR1, PRKAR2, and AKAP3 were evaluated by Western blot. The localization of pPRKAs, PRKAR1, PRKAR2, and AKAP3 was evaluated by immunofluorescence. Treatment with epoxomicin changed the localization and phosphorylation pattern and decreased the percentage of pPRKAs-positive sperm. PRKA activity significantly increased at 1 min of capacitation and remained high throughout the incubation. However, epoxomicin treatment significantly decreased PRKA activity after 30 min. In addition, PRKAR1 and AKAP3 were degraded by the proteasome but with a different temporal kinetic. Our results suggest that PRKAR1 is the target of PRKA regulation by the proteasome. Full article

(This article belongs to the Special Issue Ubiquitin–Proteasome System and Small Protein Modifiers in Gametogenesis and Fertility)

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13 pages, 4897 KiB

Open AccessArticle

Cullin4 E3 Ubiquitin Ligases Regulate Male Gonocyte Migration, Proliferation and Blood-Testis Barrier Homeostasis

by Yan Yin, Liming Zhu, Qiufang Li, Pengbo Zhou and Liang Ma

Cells 2021, 10(10), 2732; https://doi.org/10.3390/cells10102732 - 13 Oct 2021

Cited by 6 | Viewed by 2146

Abstract

Ubiquitination, an essential posttranslational modification, plays fundamental roles during mammalian spermatogenesis. We previously reported the requirement of two Cullin 4 ubiquitin ligase family genes, Cullin 4a (Cul4a) and Cullin 4b (Cul4b), in murine spermatogenesis. Both genes are required for male fertility despite their distinct functions in different cell populations. Cul4a is required in primary spermatocytes to promote meiosis while Cul4b is required in secondary spermatocytes for spermiogenesis. As the two genes encode proteins that are highly homologous and have overlapping expression in embryonic germ cells, they may compensate for each other during germ cell development. In the present study, we directly address the potential functional redundancy of these two proteins by deleting both Cul4 genes, specifically, in the germ cell lineage during embryonic development, using the germ-cell specific Vasa-Cre line. Conditional double-knockout (dKO) males showed delayed homing and impaired proliferation of gonocytes, and a complete loss of germ cells before the end of the first wave of spermatogenesis. The dKO male germ cell phenotype is much more severe than those observed in either single KO mutant, demonstrating the functional redundancy between the two CUL4 proteins. The dKO mutant also exhibited atypical tight junction structures, suggesting the potential involvement of CUL4 proteins in spermatogonial stem cell (SSC) niche formation and blood–testis-barrier (BTB) maintenance. We also show that deleting Cul4b in both germ and Sertoli cells is sufficient to recapitulate part of this phenotype, causing spermatogenesis defects and drastically reduced number of mature sperms, accompanied by defective tight junctions in the mutant testes. These results indicate the involvement of CUL4B in maintaining BTB integrity. Full article

(This article belongs to the Special Issue Ubiquitin–Proteasome System and Small Protein Modifiers in Gametogenesis and Fertility)

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19 pages, 4946 KiB

Open AccessArticle

Mammalian Cell-Free System Recapitulates the Early Events of Post-Fertilization Sperm Mitophagy

by Won-Hee Song, Dalen Zuidema, Young-Joo Yi, Michal Zigo, Zhibing Zhang, Miriam Sutovsky and Peter Sutovsky

Cells 2021, 10(9), 2450; https://doi.org/10.3390/cells10092450 - 17 Sep 2021

Cited by 7 | Viewed by 3500

Abstract

Propagation of paternal sperm-contributed mitochondrial genes, resulting in heteroplasmy, is seldom observed in mammals due to post-fertilization degradation of sperm mitochondria, referred to as sperm mitophagy. Whole organelle sperm mitochondrion degradation is thought to be mediated by the interplay between the ubiquitin-proteasome system (UPS) and the autophagic pathway (Song et al., Proc. Natl. Acad. Sci. USA, 2016). Both porcine and primate post-fertilization sperm mitophagy rely on the ubiquitin-binding autophagy receptor, sequestosome 1 (SQSTM1), and the proteasome-interacting ubiquitinated protein dislocase, valosin-containing protein (VCP). Consequently, we anticipated that sperm mitophagy could be reconstituted in a cell-free system consisting of permeabilized mammalian spermatozoa co-incubated with porcine oocyte extracts. We found that SQSTM1 was detected in the midpiece/mitochondrial sheath of the sperm tail after, but not before, co-incubation with oocyte extracts. VCP was prominent in the sperm mitochondrial sheath both before and after the extract co-incubation and was also detected in the acrosome and postacrosomal sheath and the subacrosomal layer of the spermatozoa co-incubated with extraction buffer as control. Such patterns are consistent with our previous observation of SQSTM1 and VCP associating with sperm mitochondria inside the porcine zygote. In addition, it was observed that sperm head expansion mimicked the early stages of paternal pronucleus development in a zygote during prolonged sperm-oocyte extract co-incubation. Treatment with anti-SQSTM1 antibody during extract co-incubation prevented ooplasmic SQSTM1 binding to sperm mitochondria. Even in an interspecific cellular environment encompassing bull spermatozoa and porcine oocyte extract, ooplasmic SQSTM1 was recruited to heterospecific sperm mitochondria. Complementary with the binding of SQSTM1 and VCP to sperm mitochondria, two sperm-borne pro-mitophagy proteins, parkin co-regulated gene product (PACRG) and spermatogenesis associated 18 (SPATA18), underwent localization changes after extract coincubation, which were consistent with their degradation observed inside fertilized porcine oocytes. These results demonstrate that the early developmental events of post-fertilization sperm mitophagy observed in porcine zygote can be reconstituted in a cell-free system, which could become a useful tool for identifying additional molecules that regulate mitochondrial inheritance in mammals. Full article

(This article belongs to the Special Issue Ubiquitin–Proteasome System and Small Protein Modifiers in Gametogenesis and Fertility)

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Review

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31 pages, 12265 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Sperm–Egg Interactions: What Ascidian Fertilization Research Has Taught Us

by Hitoshi Sawada and Takako Saito

Cells 2022, 11(13), 2096; https://doi.org/10.3390/cells11132096 - 1 Jul 2022

Cited by 10 | Viewed by 3122

Abstract

Fertilization is an essential process in terrestrial organisms for creating a new organism with genetic diversity. Before gamete fusion, several steps are required to achieve successful fertilization. Animal spermatozoa are first activated and attracted to the eggs by egg-derived chemoattractants. During the sperm passage of the egg’s extracellular matrix or upon the sperm binding to the proteinaceous egg coat, the sperm undergoes an acrosome reaction, an exocytosis of acrosome. In hermaphrodites such as ascidians, the self/nonself recognition process occurs when the sperm binds to the egg coat. The activated or acrosome-reacted spermatozoa penetrate through the proteinaceous egg coat. The extracellular ubiquitin–proteasome system, the astacin-like metalloproteases, and the trypsin-like proteases play key roles in this process in ascidians. In the present review, we summarize our current understanding and perspectives on gamete recognition and egg coat lysins in ascidians and consider the general mechanisms of fertilization in animals and plants. Full article

(This article belongs to the Special Issue Ubiquitin–Proteasome System and Small Protein Modifiers in Gametogenesis and Fertility)

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22 pages, 1199 KiB

Open AccessReview

Ubiquitin-Proteasome System–Regulated Protein Degradation in Spermatogenesis

by Yi Xiong, Chao Yu and Qianting Zhang

Cells 2022, 11(6), 1058; https://doi.org/10.3390/cells11061058 - 21 Mar 2022

Cited by 16 | Viewed by 4973

Abstract

Spermatogenesis is a prolonged and highly ordered physiological process that produces haploid male germ cells through more than 40 steps and experiences dramatic morphological and cellular transformations. The ubiquitin proteasome system (UPS) plays central roles in the precise control of protein homeostasis to ensure the effectiveness of certain protein groups at a given stage and the inactivation of them after this stage. Many UPS components have been demonstrated to regulate the progression of spermatogenesis at different levels. Especially in recent years, novel testis-specific proteasome isoforms have been identified to be essential and unique for spermatogenesis. In this review, we set out to discuss our current knowledge in functions of diverse USP components in mammalian spermatogenesis through: (1) the composition of proteasome isoforms at each stage of spermatogenesis; (2) the specificity of each proteasome isoform and the associated degradation events; (3) the E3 ubiquitin ligases mediating protein ubiquitination in male germ cells; and (4) the deubiquitinases involved in spermatogenesis and male fertility. Exploring the functions of UPS machineries in spermatogenesis provides a global picture of the proteome dynamics during male germ cell production and shed light on the etiology and pathogenesis of human male infertility. Full article

(This article belongs to the Special Issue Ubiquitin–Proteasome System and Small Protein Modifiers in Gametogenesis and Fertility)

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14 pages, 1378 KiB

Open AccessReview

SCF Ligases and Their Functions in Oogenesis and Embryogenesis—Summary of the Most Important Findings throughout the Animal Kingdom

by Veronika Kinterová, Jiří Kaňka, Alexandra Bartková and Tereza Toralová

Cells 2022, 11(2), 234; https://doi.org/10.3390/cells11020234 - 11 Jan 2022

Cited by 4 | Viewed by 3154

Abstract

SCF-dependent proteolysis was first discovered via genetic screening of budding yeast almost 25 years ago. In recent years, more and more functions of SCF (Skp1-Cullin 1-F-box) ligases have been described, and we can expect the number of studies on this topic to increase. SCF ligases, which are E3 ubiquitin multi-protein enzymes, catalyse protein ubiquitination and thus allow protein degradation mediated by the 26S proteasome. They play a crucial role in the degradation of cell cycle regulators, regulation of the DNA repair and centrosome cycle and play an important role in several diseases. SCF ligases seem to be needed during all phases of development, from oocyte formation through fertilization, activation of the embryonic genome to embryo implantation. In this review, we summarize known data on SCF ligase-mediated degradation during oogenesis and embryogenesis. In particular, SCF^βTrCP and SCF^SEL-10/FBXW7 are among the most important and best researched ligases during early development. SCF^βTrCP is crucial for the oogenesis of Xenopus and mouse and also in Xenopus and Drosophila embryogenesis. SCF^SEL-10/FBXW7 participates in the degradation of several RNA-binding proteins and thereby affects the regulation of gene expression during the meiosis of C. elegans. Nevertheless, a large number of SCF ligases that are primarily involved in embryogenesis remain to be elucidated. Full article

(This article belongs to the Special Issue Ubiquitin–Proteasome System and Small Protein Modifiers in Gametogenesis and Fertility)

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