August 1, 2005: Identification of a novel ubiquitin-activating enzyme E1 variant in the testis supports the importance of regulated proteolysis in human/mammalian spermatogenesis.

Commentary by Peter Sutovsky for Acta Biochimica et Biophysica Sinica

Last year's Nobel Prize in chemistry was awarded to Aaron Ciechanover, Avram Hershko and Irwin Rose for their discovery of the ATP-dependent, proteolytic ubiquitin system. Due to its unique combination of substrate specificity and high evolutionary conservation, the ubiquitin system is likely to play a role in any body function. Besides general housekeeping and protein recycling, some of the best studied examples of the function of ubiquitin system are those of cell cycle regulation, the endoplasmatic reticulum-associated protein quality control and antigen presentation within immune system (reviewed in [1]). No less important is the functioning of ubiquitin system in varied pathologies including but not limited to Alzheimer’s disease, retroviral infection (e.g. HIV) and liver cirrhosis brought about by alcohol abuse. The central dogma of the ubiquitin system is that the small chaperone protein ubiquitin, covalently linked to a substrate protein in a tandem fashion, marks the said substrate for proteolysis by the 26 S proteasome, a multi-subunit protease complex typically composed of a 19 S regulatory subunit and a 20 S core [2]. This stable but reversible postranslational modification is aided by a specific set of ubiquitin activating enzymes (E1), ubiquitin-conjugating enzymes (E2) and substrate specific ubiquitin ligases (E3).

Despite the current boom of ubiquitin research, the field of reproductive biology largely stood away from studying the ubiquitin system, with few notable exceptions including the implication of the ubiquitin system in the surveillance mechanisms for epididymal sperm maturation and organelle inheritance after fertilization (reviewed in [3]), the function of sperm acrosome-borne proteasome during fertilization [4-6], and the knock out studies of ubiquitin conjugating enzymes in the testis [7-9]. The later studies demonstrated that genetic ablation of ubiquitin conjugating enzymes in the testis can halt spermatogenesis at well defined stages, including spermatocyte meiosis [8] and spermatid elongation [9]. Several papers support this notion, showing the participation of ubiquitin system in the degradation of spermatid cytosolic proteins and organelles, and the biogenesis of sperm accessory structures [10,11].

While many enzymes of the ubiquitin system and ubiquitin itself are phylogenetically conserved, it is likely that testis-specific gene products related to the ubiquitin system and/or those derived by alternative splicing of transcripts present also in somatic cells participate in the process of spermatogenesis. Along this line, the paper by Zhu et al. [12], published last year in the Acta Biochmica et Biophysica Sinica, reports the identification of a new ubiquitin activating enzyme of E1 type, designated nUBE1L, that is predominantly expressed in the testis. Although no functional studies were performed, it appears that the enzymes is highly expressed in the adult testis, and may thus be involved in spermatogenesis. The aminoacid sequence of the nUBE1L enzyme displays typical features of an ubiquitin activating enzyme, including the Thif-domain, two UBACT domains and a conserved cysteine residue upstream of the UBACT site, implicated in the formation of thiol-ester bond with a monoubiquitin molecule during ubiquitin activation. Further, according to their observations, the authors propose that a common theme of alternative splicing of somatic-cell-like transcripts of ubiquitin-conjugating enzymes in the testis provides a mechanism guiding spermatogenesis. This is a reasonable proposition, as we see other genes not related to ubiquitin system (reviewed in [13]) being transcribed and translated in that fashion in the testis. Although the present study does not provide clues as to when and in which cell type within the testis this novel E1 enzyme functions, the report supports the view that developmentally regulated, ubiquitin-dependent proteolysis helps controlling spermatogenesis. Alternatively, it cannot be ruled out that this and/or other enzymes become sequestered in the mature spermatozoa and may be involved in epididymal sperm maturation or in the sperm function during fertilization. While similar evidence is only now being generated in mammals, studies in ascidians have shown that the complement of sperm borne ubiquitinating enzymes participated in the ubiquitination and degradation of the sperm receptor on the egg vitelline envelope [4].

Peter Sutovsky, PhD

Assistant Professor

University of Missouri-Columbia

S141 ASRC

920 East Campus Drive

Columbia, MO 65211-5300

Telephone: (573) 882-3329

Fax: (573) 884-5540

http://www.missouri.edu/~reprphys/sutovskyp.htm

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