Proteolysis in Reproduction: Lessons From Gene-Modified Organism Studies

Abstract

The physiological roles of proteolysis are not limited to degrading unnecessary proteins. Proteolysis plays pivotal roles in various biological processes through cleaving peptide bonds to activate and inactivate proteins including enzymes, transcription factors, and receptors. As a wide range of cellular processes is regulated by proteolysis, abnormalities or dysregulation of such proteolytic processes therefore often cause diseases. Recent genetic studies have clarified the inclusion of proteases and protease inhibitors in various reproductive processes such as development of gonads, generation and activation of gametes, and physical interaction between gametes in various species including yeast, animals, and plants. Such studies not only clarify proteolysis-related factors but the biological processes regulated by proteolysis for successful reproduction. Here the physiological roles of proteases and proteolysis in reproduction will be reviewed based on findings using gene-modified organisms.

Introduction

Although a simple peptide bond between two amino acids in water at room temperature has a half-life of several years (1), the hydrolysis of a peptide bond is significantly accelerated under the presence of proteases. As well as mediating non-specific protein hydrolysis, proteases also act as processing enzymes that perform highly selective, limited, and efficient cleavage of specific substrates. As many biological processes are influenced by this irreversible post-translational protein modification, dysregulation of the expression and/or function of proteases underlie many human pathological processes and have therefore been an intensely studied class of targets for drug discovery.

By searching Saccharomyces cerevisiae, Drosophila melanogaster, and Caenorhabditis elegans genome databases with a gene ontology term “peptidase activity” (GO:0008233), 51, 506, and 448 genes encoding proteases, respectively, can be identified (2–4). In the mouse and human genome, 628 and 553 protease genes exist, respectively (5). In Arabidopsis thaliana, 723 protease genes were reported (6). Based on catalytic mechanisms, proteases can be divided into five classes: cysteine proteases, serine proteases, metalloproteases, threonine proteases, and aspartic proteases. After activation of the amide, cysteine, serine, and threonine proteases utilize the namesake residue to attack the amide carbonyl group, whereas metalloproteases and aspartic proteases use an activated water molecule as a nucleophile. As proteases bind their substrates between the substrate side chains and well-defined substrate-binding pockets within the active site, they have their own preference for substrate amino acid sequence proximal to the cleavage site (7). There are some enzymatically inactive pseudoproteases encoded in the mammalian genome in which the amino acid residues indispensable for catalytic activity are substituted. As proteases are potentially toxic, their activities are strictly regulated as such by pH, specific ion concentrations, posttranslational modifications, and spatiotemporal expression of protease inhibitors.

The contribution of proteases depends on their intracellular or extracellular localization where they act on substrate proteins. The ubiquitin-proteasome system (UPS) is a complex but sophisticated intracellular proteolytic system in eukaryotes; this complex system degrades unneeded or damaged proteins by proteolysis. When target proteins are post-translationally labeled with ubiquitin, a protein of 76-amino acid residues exhibiting high sequence conservation among eukaryotes, they will be recognized and degraded by the proteasome.

Proteolytic processing events are fundamental in reproductive processes including gametogenesis, fertilization, and embryonic development. Recent advances in generating gene-modified animals have identified many proteases and their regulators associated with reproduction in various species including yeast, invertebrates, vertebrates, and plants. In the following sections the physiological importance of proteolysis in reproduction will be overviewed based on findings obtained by gene-modified organism studies. Proteolysis-related genes essential in reproduction identified by gene-modified animal studies are listed in Table 1. Few proteins are known to be proteolytically processed under certain reproductive situations. They are, however, not included in this review as the physiological roles of such processing in reproduction are not fully clarified at present.

Unicellular Organisms

Saccharomyces cerevisiae

S. cerevisiae, Baker’s yeast, is a model diploid unicellular organism. S. cerevisiae can stably exist as either a diploid or a haploid. When stressed, S. cerevisiae can undergo meiosis to produce four haploid spores. Haploid cells are capable of fusing with other haploid cells of the opposite mating type (an ‘a’ cell can only mate with an ‘α’ cell, and vice versa) to produce a stable diploid cell. a and α cells produce mating peptide pheromones a-factor and α-factor, respectively. Ste24p and Axl1p encoded by ste24 and alx1, respectively, are metalloendopeptidases that process precursor peptide to produce mature mating a-factor pheromone (8, 9).

Multicellular Organisms I: Invertebrates

The body of multicellular organisms consists of two types of cells with different lineages, i.e., germ cells and somatic cells. Germ cells produce gametes for fertilization, whereas somatic cells develop reproductive organs to support gametogenesis and fertilization by germ cells. Therefore, dysfunction of proteolysis in either cell lineage can result in fertility defects.

Nematodes

Caenorhabditis elegans is androdioecious; i.e., it has two sexes, hermaphrodite and male, whereas Ascaris suum is dioecious, being either male or female. They develop two U-shaped gonads in which gametes are generated and fertilization occurs. Several proteases and inhibitors have been identified to regulate nematode reproductive processes.

Oogenesis and fertilization are affected when cpi-2a, encoding a cystatin-like cysteine protease inhibitor, is mutated (10). Nullification of dss-1 encoding a 26S proteasome subunit provokes sterility because of deficient oogenesis (14). Knockdown of puromycin-sensitive aminopeptidase encoded by pam-1 causes delayed oocyte maturation and subfertility (17). Deletion of dpf-3 encoding a serine protease causes sterility because of impaired spermatogenesis (15). gon-1 encoding a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif (ADAMTS) is necessary for morphogenesis of U-shaped gonads (11, 12). A mutant worm lacking timp-1 encoding a tissue inhibitor of metalloproteinase also shows deficient gonadal development (13). A double mutant in which sup-17 and adm-4, encoding nematode orthologs of mammalian membrane metalloproteases ADAM10 and ADAM17, respectively, are sterile because of aberrant spermathecal function (16).

Unlike mammalian flagellated sperm, nematode sperm are amoeboid cells. For successful fertilization, sperm must be activated prior to contacting an oocyte in both C. elegans and A. suum. This sperm activation is called spermiogenesis through which round immobile spermatids transform into motile, fertilization-competent spermatozoa. Mechanistically, spermiogenesis occurs by sensing extracellular signals and can be reproduced in vitro by exposing spermatids to proteases such as Pronase and proteinase K. A trypsin-like secreted protease encoded by try-5 is expressed in the vas deferens and triggers activation of spermatids (18). swm-1 encodes a secreted protein with a trypsin inhibitor-like domain, and swm-1 mutant males are infertile because of ectopic premature activation of sperm (19). Like in C. elegans, activation of spermatozoa by exposure to extrinsic protease in vitro can also be seen in several insect species (132, 133). spe-4 encoding a presenilin, an aspartyl protease with intramembrane proteolytic activity prevents spermatid activation because spe-4 mutant males progress directly to functional spermatozoa without the need for an activation signal (134).

gcna-1 encodes nuclear metalloprotease. gcna-1 deletion causes genomic instability decreasing fertility in later generations (20). T12E12.6 encodes intracellular metalloprotease whereas zmp-2 encodes secreted metalloproteases. Knockdown of either of them results in reduced offspring production (17, 21).

Insects

The reproductive system of Drosophila melanogaster is more complex compared with nematodes; it is composed of gonads, genital ducts, and accessory structures. Several proteases have been implicated in D. melanogaster spermatogenesis. In the D. melanogaster genome, there are five genes paralogous to S. cerevisiae ste24 encoding a type I prenyl protease. Deletion of three tandemly arrayed ste24 paralogs results in male fertility defects manifesting late in spermatogenesis (22).

All Drosophila spermatid nuclei descended from a primary spermatocyte remain connected to each other via an extensive network of cytoplasmic bridges. Spermatids should therefore be physically dissociated from each other by a process referred as individualization and a ubiquitin-proteasome system regulates this process. Males in which Prosalpha6T encoding a testis-specific proteasome core particle subunit was ablated are sterile because of defects in sperm individualization and nuclear maturation (23). Duba encodes a deubiquitylating enzyme and Duba null mutants are male sterile and display defects in spermatid individualization (24). The non-apoptotic function of caspases also contributes to individualization. DARK is a Drosophila homolog of mammalian caspase activator Apaf-1, whereas DRONC and DREDD are Drosophila apical caspases. Flies deficient in DARK or expressing a dominant-negative version of DRONC failed individualization (25, 135). Dredd-null flies also often show individualization defects (25).

In D. melanogaster sperm, mitochondrial derivatives run along the entire flagellum to provide structural rigidity for flagellar movement. Two mitochondrial derivatives (i.e., major and minor) differentiate and major one accumulates paracrystalline material by the end of spermatogenesis. S-Lap1-8, Sperm-Leucylaminopeptidase (S-Lap) family members are constituents of paracrystalline material. S-Lap mutants possess defects in paracrystalline material accumulation and abnormal structure of the elongated major mitochondrial derivatives and male sterility (28). Htra2 encodes a mitochondrial serine protease. In one Htra2-null mutant line males are infertile because sperm are completely immotile (26), whereas spermatogenesis is defective in another Htra2 mutant line (27).

Seminal fluid produced in the accessory gland includes proteases and protease inhibitors and is thought to contribute to fertilization in a post-mating manner. Seminase is a trypsin-like protease encoded by Sems and included in seminal fluid. When females mated with Sems knockdown males, they laid significantly fewer eggs (29). In cricket, Allonemobius socius, an ejaculate serine protease encoded by ejac-sp is expressed in male reproductive accessory glands. RNAi knockdown of ejac-sp resulted in a significant reduction of the male’s ability to induce a female to lay eggs (38). Nep4, a drosophila ortholog of mammalian Mmel1, encodes a metalloprotease expressed in male gonads (136). Nep4 mutant males are infertile; mutant sperm are quickly discarded by females (30). When Dcp-1 encoding a cysteine protease was ablated in their germline, the resulting females were infertile because of defective oogenesis (31).

Several proteases also of concern in Drosophila reproduction include maternal haploid or mh encodes the Drosophila homolog of SPRTN, a conserved metalloprotease essential for resolving DNA–protein cross-linked products. Paternal chromatids of mh mutants are unable to separate in the anaphase of the first embryonic mitosis and form a chromatin bridge. As a consequence, haploid nuclei of maternal origin rapidly separate from the damaged paternal chromosomes and haploid embryos develop but become lethal in a maternal effect manner (32, 33, 137). Ance encodes a putative homologue of mammalian angiotensin-converting enzyme (ACE). Compound heterozygote for two different Ance lethal alleles exhibit male sterility (34), but the molecular details are unknown. RNAi knockdown of Slfc encoding a secreted serine protease causes male infertility (35). When a membrane serine protease encoded by ome was mutated, males became subfertile (36). RNAi knockdown of a secreted metalloprotease encoded by Mmp2 caused female subfertility because ovulation was blocked (37).

Several pest control attempts target reproduction-associated proteases. In pests Spodoptera litura and Plutella xylostella, targeted inactivation of serine protease genes Osp and Ser2, respectively, resulted in female and male infertility as also observed in silkworm moth Bombyx mori (39, 40). In other pests Hyphantria cunea, and Bactrocera dorsalis, RNAi knockdown of Hcser2, and Bdcp-1 encoding serine protease and cysteine protease, respectively, also resulted in infertility (41, 42). Thus, proteases are potential targets for pest population control.

Multicellular Organisms II: Vertebrates

Findings in vertebrates were obtained by genetic studies in rodents, fish, and human patients. Genes disrupted in these species include those encoding proteases, protease inhibitors, and non-catalytically active pseudo-proteases. Proteolysis-related factors are included in various aspects of male and female reproductive processes such as gamete production, gamete maturation, fertilization, post-fertilization events, and mating behavior.

UPS in Gamete Production

For the fine-tuning of cellular processes, intracellular proteins are timely degraded by UPS. The proteasome localizes in the nucleus and cytoplasm where it degrades ubiquitylated proteins. Spermatoproteasome, a testis-specific proteasome, is one of the three tissue-specific proteasomes identified together with the immunoproteasome and the thymoproteasome in mammals (138). Deletion of Psma8, which encodes a testis-specific 20S proteasome component, leads to spermatogenesis arrest at the spermatocyte stage (43). Psme3 encodes REGγ, a proteasome activator. Psme3-null males are subfertile with decreased sperm number and motility (44). This is probable because REGγ regulates p53-mediated transcription of Plzf, a transcription factor necessary for spermatogonial stem cell self-renewal and proliferation (139). Psme4 encodes PA200 proteasome activator. Psme4-null males have reduced fertility due to defects in meiotic spermatocytes and post-meiotic spermatids (45). Psme3;Psme4 double KO males were infertile; mutant sperm appeared morphologically normal but exhibited remarkable defects in motility and decreased proteasome activity (46).

Proteasome target proteins are ubiquitylated by E3 ubiquitin ligases which transfer the ubiquityl group from E2 ligase to the target protein. There are ∼600 E3 ligases encoded in the mammalian genome (140). The ubiquitin ligases, which are not proteases but included in ubiquitin-proteasome system-mediated protein degradation, indispensable for mammalian reproduction are listed in Table 2. Here only Huwe1 is mentioned as how E3 ligases function in reproductive processes. Huwe1 ubiquitylates histone H2AX, which is phosphorylated in response to DNA damage and is essential to the efficient recognition and repair of DNA double-strand breaks. Germline-specific Huwe1 ablation increased histone H2AX level, elevated DNA damage response, and caused Sertoli cell only phenotype. Thus Huwe1 likely regulates the response to spontaneous DNA damage by UPS-mediated H2AX degradation to maintain cell survival (156).

Cullin-RING E3 ubiquitin ligases are known to be reversibly neddylated, i.e., conjugated with NEDD8, a ubiquitin-like protein. By conjugation with NEDD8, cullin-RING E3 ligases increase their stability and ligase activity. The constitutive photomorphogenic-9 signalosome (CSN) deneddylates cullin-RING E3 ligases by cleaving the isopeptide bond of neddylated lysine to regulate the cellular ubiquitylation status. COPS5 is the fifth component of the CSN and abundant in mouse testis (185). Cops5-null males were infertile because of significant reduction of sperm number caused by premeiotic apoptosis of germ cells (47).

Ubiquitylated proteins can be deubiquitylated by deubiquitylating enzymes such as ubiquitin-specific proteases (USPs), cysteine endopeptidases encoded by Usp genes, thereby expression levels and activity of target proteins are regulated. USP1 deubiquitylates FANCD2 which is included in the repair of DNA crosslinks. Usp1 null males were infertile and the seminiferous tubules were markedly atrophic and mostly devoid of spermatogenic cells in the mutant testis. Usp2-null males possessed severely reduced fertility and the mutant sperm were defective in sperm motility and egg fertilizing ability in vitro (48). Germ cell-specific ablation of Usp9x using Vasa-cre possessed spermatogenic cell apoptosis at the early spermatocyte stage and resulted in complete infertility (49). Usp26 is an X-linked gene exclusively expressed in testis (186). Usp26 -null males are subfertile because of reduced number of haploid cells in testis (50, 51). Usp1-null female mice showed reduced fertility probably because of a reduced number of oocytes in ovaries (52). Thus, UPS is critically important for germ cell production in both sexes.

Non-Proteasomal Intracellular and Extracellular Proteolysis Factors in Sperm Production

Intracellular and extracellular proteolysis factors critically function in spermatogenesis. Cleavage of specific peptide bonds also contributes to spermatogenesis. Apaf1 encodes a caspase activator, and Apaf1-null males are infertile because of degeneration of spermatogonia, which results in the absence of sperm (53). Agbl5 encodes an intracellular metalloprotease. Agbl5-null males are infertile because of defective spermatogenesis (54, 55). A cytosolic carboxypeptidase 1, another metalloprotease encoded by Agtpbp1 deglutamylates polyglutamylated proteins. Agtpbp1 mutant mice known as Purkinje cell degeneration (pcd) possess male infertility (109–112) because of defective spermatogenesis (110). A germ cell nuclear antigen encoded by Gcna contains a metalloprotease domain. Gcna-null males are nearly devoid of sperm and infertile (56). In human, GCNA spontaneous mutations were identified in spermatogenic failure patients (124, 125).

Separin, a caspase-like cysteine protease encoded by Espl1, plays a central role in chromosome segregation by cleaving the SCC1/RAD21 subunit of the cohesin complex (187–189). A point mutation in Espl1 which substitutes inhibitory phosphorylation site Ser¹¹²¹ to Ala depletes spermatogonia because of chromosome misalignment during proliferation of the postmigratory primordial germ cells and following mitotic arrest, aneuploidy, and cell death (105). Threonine aspartase 1 (TASP1) is an intracellular endopeptidase that cleaves after distinct aspartate residues of the conserved IXQL(V)D/G motif (190). TASP1 cleaves general transcription factor TFIIAα−β to enable testis-specific transcription; Tasp1-null male mice were unable to activate spermatogenic gene activation, which lead to the release of immature germ cells and infertility (57). A serine protease ClpP is located in the mitochondrial matrix and participates in mitochondrial protein quality control by degrading misfolded or damaged proteins. In Clpp-null mutants spermatogenesis was disrupted by the spermatid stage (114). Tysnd1 encodes a serine protease that processes peroxisomal leader peptides. Tysnd1-null mutant males possess globozoospermia and their spermatozoa lack the acrosomal cap (58). Spink2 encodes a Kazal-type serine protease inhibitor abundantly expressed in testis and epididymis (191). Spink2-null males had azoospermia, and a homozygous splice mutation of SPINK2 was found in infertile men (59). Ablation of Serpina5 encoding another serine protease inhibitor also results in an abnormality in sperm production in the testis (60).

Puromycin-sensitive aminopeptidase encoded by Npepps is also an intracellular protease. It appears to contribute indirectly to spermatogenesis. Npepps-null testes and seminal vesicles were significantly reduced in weight, spermatogenesis was impaired, and copulatory behavior was lacking. It is suggested that the defects in the testes likely arises from dysfunction of Sertoli cells, whereas the lack of copulatory behavior results from defects in the brain (115).

A null mutation of Adamts2 encoding secreted metalloproteinase caused male infertility (61). Decreased spermatogenesis was observed but copulatory behavior and/or copulatory plug formation may also be impaired because a copulatory plug was never observed (61).

Proteolysis Factors Associated With Sperm Function

Acrosomal Function

The acrosome is a Golgi-derived sperm head organelle in which many digestive enzymes such as proteases and hyaluronidases are included to penetrate egg surroundings. Acrosin is a serine protease and a major component of the acrosome. Although acrosin-deficient male mice are fertile (62, 63), disruption of hamster acrosin resulted in complete male infertility (120). In vitro, mutant hamster spermatozoa attached to the zona pellucida, but failed to penetrate it (120), suggesting that acrosomal function can be attributed to specific factors in a species-specific manner.

Proprotein convertases convert inactive precursor proteins into their mature and active forms. PCSK4 is a member of proprotein convertases expressed on the sperm surface overlying the acrosome (64). Pcsk4-null males showed impaired fertility (64, 65) and mutant sperm exhibited accelerated capacitation, precocious acrosome reaction, reduced binding to egg zona pellucida (64). Acrosome formation during spermatogenesis was also abnormal (192).

Sperm Maturation

A group of genes encoding proteases, enzymatically inactive pseudoproteases, and protease inhibitors is apparently associated with the same physiological function, i.e., maturation of sperm conferring abilities to migrate into female oviduct and bind with zona pellucida. Ablation of Tmprss12 (66), Prss55 (67, 68), Tryx5 (69), Prss37 (70), Ace (71), Adam1a (72), Adam2 (73), Adam3 (74, 75), and Adam6 (76) results in deficient sperm migration into the oviduct and binding to the zona pellucida of eggs. Among them, Adam1a, Adam2, Adam3, Adam6, and Prss37 encode catalytically inactive pseudoproteases. A disintegrin and metallopeptidase domain (ADAM) 3, a catalytically inactive transmembrane pseudoprotease appears to be central to a molecular mechanism that governs sperm migratory and adhesion abilities, because ADAM3 expression is a prerequisite for sperm to acquire these abilities (193).

ADAM3 is expressed as a precursor and the processed into mature form as spermatozoa mature in epididymis (194). Similarly, enzymatically inactive pseudoproteases ADAM2 and ADAM6 are processed during sperm maturation in epididymis (195, 196). Therefore, they are rather substrates for other proteases. Ablation of ADAM2 or ADAM6 also results in significant decrease or loss of ADAM3 from epididymal sperm (74, 76) indicating the involvement of both ADAM2 and ADAM6 in ADAM3 expression. PRSS37 supports ADAM3 precursor translocation to the sperm cell surface by collaborating with PDILT, a testis-specific protein disulfide isomerase indispensable for ADAM3 surface expression (197, 198). TMPRSS12, PRSS55, and TRYX5, all of which are serine proteases and retain catalytic triad residues, are necessary for the production or stable localization of processed ADAM3 on the cell surface of epididymal spermatozoa (66–69), although it remains uncertain whether these proteases directly cleave ADAM3.

Cystatins are secreted cysteine proteinase inhibitors. Cystatin genes Cst8, 9, 11, 12, 13, dc1, dc2, and l1 are clustered on mouse chromosome 2 and expressed in both testis and epididymis. Their simultaneous ablation resulted in the loss of ADAM3 from epididymal sperm and deficient sperm migration into the oviduct (77), implying the importance of regulated proteolysis in sperm maturation. Ovochymase 2 (OVCH2) is a chymotrypsin-like serine protease. OVCH2 is specifically expressed in the caput epididymis under the regulation of lumicrine signaling, in which testis-derived secreted protein NELL2 transiting through the luminal space acts on the epididymal epithelium by binding to its receptor ROS1 tyrosine kinase to differentiate (78). Ablation of Ovch2 results in abnormal sperm ADAM3 processing and deficient sperm migration into the oviduct (78). Thus, regulated proteolysis on or outside spermatozoa apparently modulates sperm maturation.

NL1 encoded by Mmel1 is a zinc metallopeptidase expressed in testis. NL1 is expressed as a type II transmembrane protein but released as a soluble form. Mmel1-null mice show normal spermatogenesis but reduced egg fertilization, suggesting the role of NL1 in sperm maturation (79). It remains, however, uncertain whether NL1 is included in ADAM3-mediated sperm maturation. Testisin encoded by Prss21 is a GPI-anchored serine protease. Prss21 KO males are subfertile because mutant spermatozoa possessed decreased motility, angulated and curled tails, and fragile necks (80). In another Prss21 mutant line in vitro sperm binding to egg zona pellucida, acrosome reaction, and fertility were decreased (81).

Other Proteolytic Factors Associated With Male Reproduction

Several cell surface and extracellular proteases and inhibitors seem to regulate male fertility in more indirect manners. Adamts16 homozygous mutant rat males resulted in cryptorchidism and male sterility (121). The mutant testis undescended during development because of the failure of gubernacular migration (122). γ-glutamyltranspeptidase 1 (GGT1) is a type II transmembrane protein which cleaves γ-glutamyl bond of extracellular glutathione (γ-Glu-Cys-Gly), glutathione conjugates, and other γ-glutamyl compounds. The resulting cysteinyl-glycine is further cleaved by dipeptidase into free amino acids. Ggt1-null males are infertile because of decreased epididymal sperm number and failure in copulatory plug formation (117). Although Ggt1-null testis was small, spermatogenesis inside seminiferous tubules appeared normal and seminal vesicles were hypoplastic. As N-acetylcysteine-fed mutant mice were fertile, the observed infertility is a consequence of cysteine deficiency (117),. Carboxypeptidase E (CPE) is a metallo-carboxypeptidase and functions as a prohormone processing exopeptidase. Cpe^fat/fat males are infertile and deficient in Pro-gonadotropin-releasing hormone processing in the hypothalamus (82). ADAM24 is a metalloproteinase localized on the mature sperm surface. Adam24-null males are subfertile and polyspermic fertilization increased in vitro and in vivo, suggesting a physiological role of ADAM24 for prevention of polyspermy (83). ADAM7 is a membrane-anchored protein with a catalytically-inactive metalloproteinase domain abundantly expressed in the epididymis (199). Adam7 ablation resulted in a modest reduction of male fertility; impaired epididymal morphology and integrity may affect sperm maturation (84).

Cystatin C encoded by Cst3 is a cysteine protease inhibitor abundantly expressed in testis and epididymis. Substitution of Leu⁶⁸ to Gln is an amyloid-forming mutation found in a hereditary form of cystatin C amyloid angiopathy. Heterozygous male mice were infertile and increased levels of amyloid was observed in the epididymal fluid (85). Nonpathological function of amyloid during epididymal sperm maturation is also suggested (200).

Immp2l encodes an inner mitochondrial membrane peptidase 2-like. Immp2l-null homozygous males were severely subfertile because of erectile dysfunction (118). Tumor necrosis factor-α (TNFα) converting enzyme encoded by Adam17 is involved in the proteolytic release of the ectodomain of diverse cell surface proteins. Conditional ablation of Adam17 with Sox9-cre severely impaired male fertility but the details are uncertain (119).

Serpine2 encodes protease nexin-1, a serine protease inhibitor expressed in seminal fluid. Serpine2-null males possessed reduced fertility because of impaired semen coagulation and copulatory plug formation (86).

Proteolytic Factors in Ovary and Follicle Development

Both intracellular and extracellular proteolytic factors are included in ovary and follicle development. Conditional ablation of separase under the control of Zp3-cre hindered extrusion of the first polar body and caused female sterility (106). Introduction of a Ser¹¹²¹ to Ala deregulatory mutation into separase led to primordial germ cell apoptosis during embryonic oogenesis (107). Ablation of cytosolic carboxypeptidase 1 encoded by Agtpbp1 results in female subfertility because secondary follicles poorly develop into antral follicles (113). Oocyte-specific ablation of nuclear cysteine protease separase causes female infertility because mutant oocytes are able neither to extrude polar bodies in meiosis I nor to resolve chiasmata (106).

A deregulatory mutation into separin encoded by Espl1 at early embryonic period caused primordial germ cell depletion by apoptosis during embryonic oogenesis, which led to female infertility (105, 107). The introduction of the same mutation at later oocyte development by using Zp3-cre also resulted in female infertility but because of failure in preimplantation development (108).

Matriptase encoded by Tmprss6 is a type II transmembrane serine protease which functions in iron homeostasis by cleaving cell surface proteins associated with iron absorption. Tmprss6-null females possessed marked retardation in ovarian maturation (87), probably because of severe decrease in plasma iron levels. The defective ovarian follicle development and female infertility can be mimicked by a low iron diet (201).

The inter-α-trypsin inhibitor (IαI) family are abundantly found in body fluids including blood plasma and urine and possess inhibitory activity for serine proteases. They are composed of bikunin, a proteoglycan with a single chondroitin sulfate chain, and heavy chains covalently bound to chondroitin sulfate chain of bikunin. IαI family members are able to transfer their heavy chains from IαI to hyaluronan in the presence of tumor necrosis factor-stimulated gene-6. This reaction results in the modified hyaluronan covalently linked heavy chain and is necessary for hyaluronan-rich cumulus matrix expansion. When the bikunin-coding region was deleted from Ambp gene, the resulting homozygous females ovulate oocytes deficient in hyaluronan-rich cumulus matrix expansion, leading to female infertility (88, 89).

γ-secretase is an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins. Psen1 encodes presenillin-1, a catalytic subunit of γ-secretase. Female mice homozygous with a Leu¹⁶⁶ to Pro mutation, an aggressive mutation found in familial Alzheimer’s disease patients, are infertile and their ovaries consisted largely of stromal elements with primordial follicles near the cortex (90).

ADAMTS1 is a secreted metalloproteinase expressed in the granulosa cell layer of mature follicles in the ovary (91). Adamts1-null females possessed lower numbers of mature follicles in the ovary and a thick and convoluted uterus (92). In another mutant mouse line, ovulation in null females was impaired because mature oocytes remained trapped in ovarian follicles (91). In zebrafish, adamts9-null females possess ovarian malformation and are unable to ovulate (123).

Lonp encodes a mitochondrial serine protease. Oocyte-specific Lonp ablation by Gdf9-cre or Zp3-cre; Lonp1^fl/fl results in female infertility because of impaired follicular development, progressive oocyte death, ovarian reserve loss (93). Furin encodes a transmembrane serine protease localized in Golgi appratus, endosome, plasma membrane; it is necessary for mature protein release by cleaving at RX(K/R)R consensus motif. Conditional ablation of Furin by Gdf9-cre or Zp3-cre; Furin^fl/fl result in female infertility because of the arrested oogenesis at early secondary follicles (94). Pappa encodes an extracellular metalloprotease. Pappa KO females decreased their litter size and ovulatory capacity, probably because of decreased bioavailability of ovarian insulin-like growth factor (95).

Loss of GGT1 causes infertility in not only males but females. In the Ggt1-null females, antral follicles and corpora lutea were absent and follicles degenerated due to the reduced intracellular cysteine levels (117).

Mitochondrial proteases also affect ovarian follicle development. Ablation of Clpp encoding mitochondrial matrix ClpP protease caused relatively small ovaries in which follicular differentiation was impaired probably because of the reduction of the granulosa cell layers (114). When the inner mitochondrial membrane peptidase 2-like encoded by Immp2l was ablated, the resulting mutant females were deficient in folliculogenesis and ovulation and infertile, probably because of low availability of nitric oxide caused by mitochondrial dysfunction (118).

Proteolytic Factors in Post-Fertilization Events of Female Reproduction

Several proteolysis-associated secreted proteins contribute to post-fertilization events including the hardening of the egg-surrounding zona pellucida. Ovastacin encoded by Astl is a secreted metalloendopeptidase deposited in cortical granules of oocytes. Ovastatin is secreted into the extracellular space in response to egg activation triggered by fertilization. In Astl-null eggs, ZP2 cleavage necessary for zona pellucida hardening and the postfertilization block to polyspermy did not occur after fertilization (96). Fetuin is a cystatin family protease inhibitor abundantly expressed in blood plasma. Fetuin-B prevents premature ZP hardening probably by inhibiting ovastacin derived from spontaneous cortical granule release, as fetuin-B inhibited ovastacin protease activity in vitro and Fetub-deficient oocytes undergo premature zona pellucida hardening (97).

Antithrombin encoded by Serpinc1 inhibits thrombin and some other coagulation factors by binding heparin and heparan sulfate. When an Arg⁴⁸ to Cys mutation, which corresponds to human thrombosis mutation, was introduced into mice, the resulting homozygous females had decreased their litter size, probably because thrombosis occurred in placenta (98).

Adam10 encodes a membrane metalloprotease. Conditional ablation of vascular Adam10 by Tie2-Cre; Adam10^fl/fl causes impaired decidualization and female subfertility (99). Adamts18 encodes a member of secreted metalloprotease ADAMTS. Adamts18-null females suffer from vaginal obstruction, due to either a dorsoventral vaginal septum or imperforate vagina and infertility or subfertility (100).

Other Proteolytic Factors in Female Reproduction

Several proteolysis-associated factors regulate female reproduction in a more indirect manner. Npepps-null females lacking a puromycin-sensitive aminopeptidase impairs corpus luteum formation and are infertile, probably because of disruption of the hypothalamic-pituitary axis (116). Plasmin is a secreted serine protease generated from plasminogen through activation by tissue-type or urokinase-type plasminogen activators. The fertility of plasmin-deficient Plg-null female mice appeared to be compromised (101, 102). It seems not to be the consequence of the impaired proteolytic process essential for ovulation, as plasminogen-deficient mice had normal ovulation efficiency (202). Timp1 encodes a tissue inhibitor of metalloproteinases 1, an inhibitor for matrix metalloproteinases. Timp1 mutation reduced the reproductive lifespan of female but not male mice (103). When Pcsk2 encoding neuroendocrine convertase 2 was ablated, the number of consecutive litters from mutant female mice was small and Pcsk2-null female mice sometimes gave birth to dead pups (104) for uncertain reason. Conditional ablation of TNFα converting enzyme by Sox9-cre; Adam17^fl/fl resulted in female infertility but details are uncertain (119).

Fertility-Associated Proteases in Plants

Several aspartic proteases are associated with pollen development and function. In Arabidopsis thaliana, A36 and A39 are GPI-anchored putative aspartic proteases predominantly expressed in pollen and the pollen tube. In a36; a39 double mutant, pollen grains underwent apoptosis-like programmed cell death and the pollen tube compromised micropylar guidance (126). UND encodes a secreted aspartic protease UNDEAD, and its silencing using small interfering RNA caused premature tapetal and pollen programmed cell death (128).

In Oryza sativa, OsAP65 encodes an aspartic protease localized in the pre-vacuolar compartment. T-DNA-inserted OsAP65 mutant alleles could not be transmitted through the male gamete; the mutant pollen matured normally, but did not germinate or elongate, indicating its essentiality in pollen germination and tube growth (131). PCS1 encodes an aspartic protease and its loss-of-function mutation caused degenerated male and female gametophytes (127).

A cysteine protease also contributes to pollen development; when a papain-like vacuolar cysteine protease encoded by CEP1 was ablated, the resulting mutants are male subfertile because of aborted tapetal programmed cell death and decreased pollen fertility with abnormal pollen exine (129).

Some aspect of A. thaliana reproduction includes Small Ubiquitin-related Modifier (SUMO). SPF1 and SPF2 are cysteine proteases and function in desumoylation of sumoylated proteins. spf1; spf2 double mutants exhibit severe abnormalities in microgametogenesis, megagametogenesis, and embryo development (130). There are SUMO-E3 ligases involved in gametophyte development (182, 183) in A. thaliana and in anther dehiscence in O. sativa (184).

Conclusion and Perspective

By a comprehensive survey, it has been demonstrated that proteolysis regulates reproduction in various species including yeast, insects, nematodes, vertebrates, and plants. Regulation of reproduction by proteolysis already exist in unicellular yeast. In multicellular organisms, proteolysis regulates the formation and function of gametes derived from germ cells as well as the development and function of reproductive organs by somatic cells, thereby securing successful reproduction. In these cell lineages, both limited proteolysis and degrative proteolysis by ubiquitin-proteasome system play critical roles.

One of intriguing paradigms emerging in this review is that many sperm surface and extracellular proteases, pseudoproteases, and inhibitors are included in the acquisition of mammalian sperm conferring abilities to migrate into the oviduct and to bind to the zona pellucida of eggs. As spermatozoa are transcriptionally and translationally silent, post-translational modification mechanisms such as proteolysis may largely contribute to sperm maturation.

Many compounds have been designed to inhibit the enzymatic activity of proteases. Clinically, there have been numerous successes including angiotensin-converting enzyme inhibitors for cardiovascular disorders (203), thrombin inhibitors for thromboembolism and bleeding disorders (204, 205), and HIV protease inhibitors in the treatment of HIV and AIDS (206), among others (207, 208). In addition, enzymatically active proteases could also be good druggable targets for contraceptives.

Genome editing techniques developed in recent years will identify fertility-associated proteolytic factors further. In addition to identifying novel factors, more intense studies on the molecular basis of proteolysis including the identification of substrates will clarify how proteolytic events govern reproduction. It will also clarify the physiological significance of molecular events governed by proteolysis in reproduction.

Funding

This work was supported in part by Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS) KAKENHI grants (JP21H00231 to D.K. and JP21H05033 to MI), Japan Science and Technology Agency (21460710 to D.K. and 21467777 to MI), National Institutes of Health (R01HD088412 and P01HD087157 to MI), and the Bill & Melinda Gates Foundation (Grant INV-001902 to MI). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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