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.

Proteomic analysis reveals dynamic changes in cloacal fluid composition during the reproductive season in a sexually promiscuous passerine

“…Although the protein composition differs between the receptive phases and GO also changes, we observed some similarities between REC-BL and REC-L. We show that positively correlated GO terms associated with regulation of proteolysis are common to both phases of receptivity (proteins OVAL, OVALY, RARRES1, CST3, SERPINB10B in REC-BL; OVAL, OVALY, RARRES1 in REC-L). The regulation of proteolysis is essential for maintaining the proper functioning of the female reproductive system and is critical for processes such as ovulation and fertilization 93 . Moreover, protease inhibitors have been shown to possess potent antimicrobial activity by effectively suppressing the activity of bacterial proteases, thus preventing the proliferation of pathogenic microorganisms 94 , which could be of a special importance in defense against sexually transmitted diseases, especially in promiscuous species such as the barn swallow 95 .…”

Proteins journey—from marine to freshwater ecosystem: blood plasma proteomic profiles of pink salmon Oncorhynchus gorbuscha Walbaum, 1792 during spawning migration

“…The most prominent LECT2 is due to its potential role in fish inflammatory response during pathogenic infection ( Shi et al, 2012 ). Protease enzymes are involved in various aspects of male and female reproductive processes, including gametogenesis and maturation, fertilization, post-fertilization events, and mating behaviour ( Kiyozumi and Ikawa, 2022 ). In the muscles of wild sockeye salmon, changes in metabolic processes during migration to the spawning site in the river have been observed.…”

Lumicrine signaling: Extracellular regulation of sperm maturation in the male reproductive tract lumen

“…A disintegrin and metalloproteinase (ADAM) 3, a catalytically inactive pseudo-metalloproteinase, is abundantly expressed on the sperm surface. The processing or truncation of sperm cell surface ADAM3 appears critical to the acquisition of fertilizing ability by sperm during their maturation in the epididymis (Kiyozumi, 2022;Kiyozumi & Ikawa, 2022), but it is critically affected in the cauda spermatozoa of lumicrinedeficient Nell2 KO, Nicol KO, or Ros1 KO mice (Kiyozumi et al, 2020(Kiyozumi et al, , 2023. Ovochymase2 (OVCH2), a secreted serine protease, has been identified as a candidate ADAM3 processing enzyme (Kiyozumi et al, 2020).…”

“…Collectively, the data suggest that OVCH2 when secreted into the epididymal lumen acts on the spermatozoa and processes cell surface proteins such as ADAM3 to make sperm fully mature. It is currently uncertain whether OVCH2 processes ADAM3 directly; it may act indirectly through the several sperm surface proteases implicated in sperm ADAM3 processing (Kiyozumi & Ikawa, 2022).…”

“…Aberrant sperm ADAM3 processing is also observed in mice lacking these epididymal secreted proteins (Fujihara et al, 2019; Krutskikh et al, 2012). Despite the uncertainty of their biochemical role in such processes, many proteases, pseudoproteases, and putative protease inhibitors are of interest because of their association with ADAM3 processing and sperm maturation (Kiyozumi & Ikawa, 2022). The precise molecular mechanism of how this luminal environment regulates sperm maturation remains to be clarified further at the molecular level.…”