Ubiquitin-dependent and independent roles of SUMO in proteostasis

Abstract

Cellular proteomes are continuously undergoing alterations as a result of new production of proteins, protein folding, and degradation of proteins. The proper equilibrium of these processes is known as proteostasis, implying that proteomes are in homeostasis. Stress conditions can affect proteostasis due to the accumulation of misfolded proteins as a result of overloading the degradation machinery. Proteostasis is affected in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and multiple polyglutamine disorders including Huntington's disease. Owing to a lack of proteostasis, neuronal cells build up toxic protein aggregates in these diseases. Here, we review the role of the ubiquitin-like posttranslational modification SUMO in proteostasis. SUMO alone contributes to protein homeostasis by influencing protein signaling or solubility. However, the main contribution of SUMO to proteostasis is the ability to cooperate with, complement, and balance the ubiquitin-proteasome system at multiple levels. We discuss the identification of enzymes involved in the interplay between SUMO and ubiquitin, exploring the complexity of this crosstalk which regulates proteostasis. These enzymes include SUMO-targeted ubiquitin ligases and ubiquitin proteases counteracting these ligases. Additionally, we review the role of SUMO in brain-related diseases, where SUMO is primarily investigated because of its role during formation of aggregates, either independently or in cooperation with ubiquitin. Detailed understanding of the role of SUMO in these diseases could lead to novel treatment options.

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

“…The ubiquitin conjugation pathway plays a key role in degrading unneeded cellular proteins, and SUMOylation is a major component of the system that controls the quality of newly synthesized proteins 10, 11, 12. UPR is a highly conserved pathway activated in stress conditions that impair proteostasis and result in accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) 9.…”

SUMO1‐conjugation is altered during normal aging but not by increased amyloid burden

“…Strikingly, we did not detect any significant link between global SUMO1 levels and AD‐like pathology. This finding argues against an involvement of altered SUMO1 conjugation in the pathogenesis of AD, at least as it is apparent in the 5XFAD model, but does not exclude a link to SUMO2/3 conjugation in this model, as SUMO2/3‐conjugation is prone to react more robustly to stress (Bernstock et al., 2018; Liebelt & Vertegaal, 2016). …”

“…As proof of principle, we found that the SUMO1 candidates identified by anti‐HA‐based affinity purification followed by mass spectrometric protein quantification were also reported in previous proteomic screens (Table S1, KI‐enriched Sheet), indicating that a large portion of the SUMO1 proteome remains stable, irrespective of the physiological context (Becker et al., 2013; Tirard et al., 2012). Many of the identified candidates are transcriptional regulators (Bcl11a/Ctip1, Bcl11b/Ctip2, Wiz, SmchD1, Trim28), indicating that the main function of SUMO1 conjugation is to guard nuclear functions, as may be particularly the case during age‐related proteostasis stress (Gartner & Muller, 2014; Hendriks & Vertegaal, 2016; Liebelt & Vertegaal, 2016). …”

“…The role of SUMOylation is particularly interesting in the context of neurodegenerative disorders with deregulated proteostasis (Feligioni et al., 2015; Krumova & Weishaupt, 2013; Lee, Sakurai, Matsuzaki, Arancio & Fraser, 2013; Liebelt & Vertegaal, 2016). Notably, SUMOylation can regulate the solubility of various disease‐associated proteins (Krumova & Weishaupt, 2013; Lee et al., 2013; Shahpasandzadeh et al., 2014).…”

“…Additionally, SUMOylation levels have been correlated to synaptic plasticity and cognitive function in normal physiology and amyloid beta pathology (Lee et al., 2014; Marcelli et al., 2017). Therefore, understanding the role of SUMOylation is particularly interesting not only during age‐related neurodegenerative stress such as AD but also during physiological aging (Andreou & Tavernarakis, 2009; Feligioni et al., 2015; Krumova & Weishaupt, 2013; Liebelt & Vertegaal, 2016). …”