Ubiquitin-Proteasome System-Regulated Protein Degradation in Spermatogenesis

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.

Keywords: E3 ubiquitin ligase; deubiquitinating enzyme (DUB); meiosis; proteasome; spermatogenesis; ubiquitination.

Figure 1

The processes of mammalian spermatogenesis. In males, primordial germ cells (PGCs) are specialized at early stages of fetal development and are arrested at G1 phase. After birth, PGCs differentiate to give rise to spermatogonia in male gonads, or testis. Spermatogonia undergo several rounds of mitosis to produce Asingle (As), Apaired (Apr), Aaligned (Aal), A1–4, intermediate and B types of spermatogonia, progressively. Type B spermatogonia are able to enter meiosis in response to the retinoic acid (RA) signalling. Through homologous recombination and synapsis at Prophase I, homologous chromosome segregation at Metaphase I and sister chromatids separation at Metaphase II, one spermatocyte divides to form 4 haploid round spermatids with ploidy reduction. Following the process of spermiogenesis, round spermatids mature to become spermatozoa with the capacity to fertilize MII eggs. The timelines of spermatogenesis in mouse and human are indicated (not to scale). The degradation timing of regulatory proteins involved in meiotic prophase I (Prophase I proteins) and histones as substrates of UPS, as well as the expression pattern of 20S proteasome subunits PSMA7 and PSMA8 are labeled with Gradient bar.

Figure 2

The schematic showing the functions of the UPS to regulate protein homeostasis during spermatogenesis. In male germ cells, the stability of proteins (or substrates here) are tightly regulated by the UPS system, including the E3 ubiquitin ligase that tags substrates for ubiquitination and the DUB that removes ubiquitin (ub) chain from the substrates to recycle both ubiquitin and substrates. Proteasomes are capable of degrading ubiquitin-linked substrates for proteolysis or degradation. So far, there are at least four types of proteasomes in testes (19S-c20S, 19S-s20S, PA200-c20S, PA200-s20S), probably expressed in different stages with distinct functions during spermatogenesis (A,B). RAD51, RPA1 and SYCP3, which are involved in synapsis and homologous recombination, are largely degraded by 19S-s20S proteasome to mediate meiotic progression; correspondingly, the unique substrates and functions for 19S-c20S proteasome remain to be explored (A). PA200 subunit is responsible for the degradation of acetylated histones to promote histone-to-protamine replacement during spermiogenesis; and it remains to be determined whether c20S or s20S is involved in this process (B).