A deficiency in SUMOylation activity disrupts multiple pathways leading to neural tube and heart defects in Xenopus embryos

Abstract

Background Adenovirus protein, Gam1, triggers the proteolytic destruction of the E1 SUMO-activating enzyme. Microinjection of an empirically determined amount of Gam1 mRNA into one-cell Xenopus embryos can reduce SUMOylation activity to undetectable, but nonlethal, levels, enabling an examination of the role of this post-translational modification during early vertebrate development. Results We find that SUMOylation-deficient embryos consistently exhibit defects in neural tube and heart development. We have measured differences in gene expression between control and embryos injected with Gam1 mRNA at three developmental stages: early gastrula (immediately following the initiation of zygotic transcription), late gastrula (completion of the formation of the three primary germ layers), and early neurula (appearance of the neural plate). Although changes in gene expression are widespread and can be linked to many biological processes, three pathways, non-canonical Wnt/PCP, snail/twist, and Ets-1, are especially sensitive to the loss of SUMOylation activity and can largely account for the predominant phenotypes of Gam1 embryos. SUMOylation appears to generate different pools of a given transcription factor having different specificities with this post-translational modification involved in the regulation of more complex, as opposed to housekeeping, processes. Conclusions We have identified changes in gene expression that underlie the neural tube and heart phenotypes resulting from depressed SUMOylation activity. Notably, these developmental defects correspond to the two most frequently occurring congenital birth defects in humans, strongly suggesting that perturbation of SUMOylation, either globally or of a specific protein, may frequently be the origin of these pathologies. Electronic supplementary material The online version of this article (10.1186/s12864-019-5773-3) contains supplementary material, which is available to authorized users.

The Function of SUMOylation and Its Critical Roles in Cardiovascular Diseases and Potential Clinical Implications

“…SUMO and SENP2 dynamically regulate the SUMOylation level of target proteins (Figure 1), and SUMOylation is an important dynamic reversible post-translational modification (PTM) to regulate protein stability, subcellular localization, and function [25]. Disorders of SUMOylation affect the normal function of target proteins and lead to the damage of important physiological processes and an abnormal intracellular environment [26]. Protein homeostasis is indispensable, especially in cells with low mitotic activity such as neurons and cardiomyocytes, to maintain cellular function [27,28].…”

SUMO proteins in the cardiovascular system: friend or foe?

“…Gam1, an adenovirus protein, selectively leads to the degradation of SUMO E1 activating enzyme [ 11 ]. Microinjections of Gam1 mRNA in embryos at different developmental stages revealed sensitivity of non-canonical Wnt/PCP, Ets-1 and snail/twist to the loss of SUMOylation [ 8 ]. This loss of SUMOylation further manifested in defects of neural tube formation and heart development [ 8 ].…”

“…Microinjections of Gam1 mRNA in embryos at different developmental stages revealed sensitivity of non-canonical Wnt/PCP, Ets-1 and snail/twist to the loss of SUMOylation [ 8 ]. This loss of SUMOylation further manifested in defects of neural tube formation and heart development [ 8 ]. Importantly, Wang et al demonstrated atrial and ventricular septal defects leading to premature death of SUMO1-deficient mice [ 109 ].…”

Influence of Sox protein SUMOylation on neural development and regeneration

“…In Drosophila, only one SUMO has been found (smt3) (Urena et al, 2016) whereas four types of SUMOs (SUMO1/2/3/4) have been identified in humans (Sarge and Park-Sarge, 2011). Unlike the process of ubiqitination leading to protein degradation (Schmidt et al, 2021), SUMOylation, a PTM which attaches SUMO to a lysine residue of protein, does not lead to protein degradation (Savare et al, 2005), and is broadly studied in plants (Augustine and Vierstra, 2018), fruit flies (Nie et al, 2009;Koltun et al, 2017) and frogs (Bertke et al, 2019). There are three enzymatic activities that contribute to the SUMOylation process including E1 SUMO1 activating enzyme subunit 1/2 (Lois and Lima, 2005), E2 ubiquitin conjugating enzyme (Reverter and Lima, 2005), and E3 ligases such as RNA binding protein 2 and protein inhibitor of activated STAT1 (PIAS1) (Morozko et al, 2021).…”