The role of E3 ligases in the ubiquitin-dependent regulation of spermatogenesis

Abstract

The ubiquitination of proteins is a post-translational modification that was first described as a means to target misfolded or unwanted proteins for degradation by the proteasome. It is now appreciated that the ubiquitination of proteins also serves as a mechanism to modify protein function and cellular functions such as protein trafficking, cell signaling, DNA repair, chromatin modifications, cell-cycle progression and cell death. The ubiquitination of proteins occurs through the hierarchal transfer of ubiquitin from an E1 ubiquitin-activating enzyme to an E2 ubiquitin-conjugating enzyme and finally to an E3 ubiquitin ligase that transfers the ubiquitin to its target protein. It is the final E3 ubiquitin ligase that confers the substrate specificity for ubiquitination and is the focus of this review. Spermatogenesis is a complex and highly regulated process by which spermatogonial stem cells undergo mitotic proliferation and expansion of the diploid spermatogonial population, differentiate into spermatocytes and progress through two meiotic divisions to produce haploid spermatids that proceed through a final morphogenesis to generate mature spermatozoa. The ubiquitination of proteins in the cells of the testis occurs in many of the processes required for the progression of mature spermatozoa. Since it is the E3 ubiquitin ligase that recognizes the target protein and provides the specificity and selectivity for ubiquitination, this review highlights known examples of E3 ligases in the testis and the differing roles that they play in maintaining functional spermatogenesis.

Keywords: E3 ligase; Spermatogenesis; Ubiquitin; Ubiquitination.

Figure 1

The process of ubiquitination. (A) Conjugation of ubiquitin (Ub) to its target protein requires the hierarchal transfer of ubiquitin from an E1 ubiquitin-activating enzyme (ATP-dependent) to an E2 ubiquitin conjugating enzyme and finally to an E3 ubiquitin ligase that confers the substrate specificity to ubiquitinate the target protein. HECT or Ring E3 ligases are the two major E3 ligase family members. A family of deubiquitinating (DUB) enzymes act to modulate the ubiquitination of proteins. (B) The specific lysine (K) amino acid of ubiquitin that links to the protein and the length of the ubiquitin change determines if the ubiquitinated protein is targeted to the proteasome for degradation or if the protein has an altered function. Polyubiquitinated proteins linked to the K48 of ubiquitin are directed to the proteasome for degradation. The mammalian 26S proteasome is composed of the 19S regulatory particle and the 20S particle containing the α and β subunits that create four stacked rings of proteins with the active protease sites inside on the face of the β subunits. Proteins linked to monomers of ubiquitin at K48 or chains of ubiquitin linked by K63 have a non-proteolytic influence on the proteins activity and function.