SUMO Family
The small ubiquitin-like modifier (SUMO) protein is about 10 ku and has a three-dimensional structure similar to ubiquitin. As an important form of reversible protein post-translational modification, SUMOylation plays an important role in protein activity, localization, and stability. It is known that four subtypes of SUMO proteins are mainly encoded in the human genome, namely SUMO1, SUMO2, SUMO3, and SUMO4. At the amino acid level, SUMO2 shares 97% identity with SUMO3 (SUMO2/3), while it shares only 46% identity with SUMO1. SUMO4 is mainly expressed in immune tissues such as the kidney, spleen tissue, and lymph nodes.
Molecular Mechanism of SUMOylation
Similar to the ubiquitination process, SUMOylation involves the attachment of a small polypeptide called ubiquitin-like modifier protein. In mammals, SUMO proteins (SUMO 1-4) are covalently attached to lysine residues in a specific SUMO consensus motif on target proteins. This process requires three enzymatic reactions: an E1 activating enzyme, an E2 conjugating enzyme, and an E3 protein ligase. SENPs , SUMO-specific proteases, play a role in regulating the SUMO cycle by removing SUMO from modified proteins and processing inactive SUMO into a mature form that can be conjugated to target proteins. Compared to ubiquitination, SUMOylation is less complex and has fewer redundancies among enzymes. Additionally, there is no overlap between the enzymes involved in the ubiquitination and SUMOylation conjugation cascades.
Fig.1 The SUMOylation reaction (Rodriguez A., Pangas S.A. 2016)
Regulation of Germ Cell Function by SUMOylation
It is reported that about 15% of couples of childbearing age worldwide are struggling with infertility, with a total number exceeding 186 million, the majority of whom are from developing countries. Among those infertility cases, over 50% are caused by female infertility. The three main factors causing female infertility are implantation failure of the embryo, inability of the uterus to become receptive, and failure of endometrial transformation. Among these three factors, abnormal embryo development leading to implantation failure is the main reason for early pregnancy loss.
SUMOylation is a highly effective strategy for regulating the activity of various developmental regulatory factors and has been confirmed in relevant studies on embryos. SUMOylation is involved in all known mechanisms that influence cell development, including transcriptional regulation, protein stability, and protein trafficking within cells. The process of SUMOylation is induced by the microenvironment and many factors, with its main function being the induction of embryonic development. Abnormal SUMOylation modification can potentially lead to defects in pre-implantation embryos, developmental defects, and embryonic lethality.
Components of the SUMO pathway play crucial roles in early mammalian embryonic development and subsequent organogenesis processes.
1. SUMO proteins
In addition to tissue-specific expression of SUMO4, mammals mainly express three types of SUMO proteins (SUMO1-3). SUMO1-3 are widely expressed throughout the whole process of mouse embryonic development. Research has shown that the loss of SUMO3 does not result in obvious phenotypes, while the loss of SUMO2 leads to embryonic lethality, and trap mutant of the SUMO1 gene results in craniofacial defects in heterozygous embryos.
2. E2 enzyme (Ubc9)
Ubc9, as the protein encoded by a single gene in the SUMO modification pathway, is the sole SUMO E2 enzyme, and its loss completely eliminates SUMOylation. In mouse embryonic development, Ubc9-deficient embryos show severe defects in chromosome segregation, leading to early embryonic death after implantation and selective apoptosis of cell clusters in the embryonic blastocyst.
3. E3 ligase (PIAS)
The PIAS family in mammals includes five subtypes: PIAS1, PIAS3, PIASxα, PIASxβ, and PIASy. It has been reported that approximately 90% of PIAS1-deficient embryos die between E10.5 and E12.5, with defects in red blood cells and blood vessel formation in the yolk sac. In addition, damage to the myocardial mass also impairs heart development during fetal development.
4. SENPs
Six SENP members have been identified in humans: SENP1, SENP2, SENP3, SENP5, SENP6, and SENP7. Embryos of SENP-knockout mice reported so far do not survive to birth, suggesting that SENPs have no redundant roles and have specific substrate specificities.
In summary, SUMOylation is of great significance for understanding normal developmental processes and pathological processes. It provides new ideas and methods for studying and preventing certain reproductive diseases and merits further in-depth research in the future.
References
- Talamillo A.; et al. The role of SUMOylation during development. Biochemical Society Transactions. 2020, 48(2): 463-78.
- Rodriguez A.; Pangas S.A. Regulation of germ cell function by SUMOylation. Cell and Tissue Research. 2016, 363: 47-55.
.
