Transforming Growth Factor-β-independent Regulation of Myogenesis by SnoN Sumoylation
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Recent progress has been made on the role of oncoproteins c-Ski and related SnoN in the control of cellular transformation. c-Ski/SnoN potently repress transforming growth factor-β (TGF-β) antiproliferative signaling through physical interaction with signal transducers called Smads. Overexpression of c-Ski/SnoN also induces skeletal muscle differentiation, but how c-Ski/SnoN function in myogenesis is largely unknown. During our investigation on the role of sumoylation in TGF-β signaling, we inadvertently found that SnoN is modified by small ubiquitin-like modifier-1 (SUMO-1). Here, we biochemically characterize SnoN sumoylation in detail and report the physiological function of the modification. Sumoylation occurs primarily at lysine 50 (Lys-50). PIAS1 and PIASx proteins physically interact with SnoN to stimulate its sumoylation, thus serving as SUMO-protein isopeptide ligases (E3) for SnoN sumoylation. SnoN sumoylation does not alter its metabolic stability or its ability to repress TGF-β signaling. Notably, loss of sumoylation in the Lys-50 site (via a Lys-to-Arg point mutation) potently activates muscle-specific gene expression and enhances myotube formation. Our study suggests a novel role for SUMO modification in the regulation of myogenic differentiation.Summary The ubiquitin-proteasome system (UPS) removes damaged and unwanted proteins by attaching ubiquitin to lysines in a process termed ubiquitination. Little is known how functional components of the UPS, often exposed to erroneous labeling by ubiquitin during functioning, avoid premature proteolysis. An extensive lysine-less region (lysine desert) in the yeast E3 ligase Slx5 was shown to counteract its ubiquitin-dependent turnover. We conducted bioinformatic screens among prokaryotes and eukaryotes to describe the scope and conservation of this phenomenon. We found that lysine deserts are widespread among bacteria using pupylation-dependent proteasomal degradation, an analog of the UPS. In eukaryotes, lysine deserts appear with increasing organismal complexity, and the most evolutionarily conserved are enriched in the UPS members. Using VHL and SOCS1 E3 ligases, which elongate their lysine desert in the course of evolution, we established that they are non-lysine ubiquitinated, which does not influence their stability, and can be subject to proteasome turnover irrespective of ubiquitination. Our data suggest that a combination of non-lysine ubiquitination and ubiquitin-independent degradation may control the function and fate of the lysine-deficient proteome, as the presence of lysine deserts does not correlate with the half-life.
Proteolysis
Protein Degradation
Proteome
Ubiquitin-Protein Ligases
Protein turnover
Ubiquitin-conjugating enzyme
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SUMO (small ubiquitin-related modifier) is involved in the post-translational modifications of proteins,and this process is referred to as SUMOylation.SUMOylation plays an important role in the regulation of cellular activities such as strengthening the stability of the protein,nucleocytoplasmic transport,DNA repair,DNA replication,mitotic and meiotic chromosome behavior,et al.SUMOylation is a dynamic process and can be reversed by SUMO-specific proteases (SENP).Once the balance between SUMOylation and de-SUMOylation is broken,there will be an aberrant expression of SUMO or SENPs in cells to happen,which may lead to the tumor occturtrence.
Key words:
Sumoylation; Amino acid motifs; Neoplasms
SUMO enzymes
RNF4
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F-box protein
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α-Synuclein accumulation is a pathological hallmark of Parkinson's disease (PD). Ubiquitinated α-synuclein is targeted to proteasomal or lysosomal degradation. Here, we identify SUMOylation as a major mechanism that counteracts ubiquitination by different E3 ubiquitin ligases and regulates α-synuclein degradation. We report that PIAS2 promotes SUMOylation of α-synuclein, leading to a decrease in α-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggregation into inclusions. This was associated with an increase in α-synuclein release from the cells. A SUMO E1 inhibitor, ginkgolic acid, decreases α-synuclein levels by relieving the inhibition exerted on α-synuclein proteasomal degradation. α-Synuclein disease mutants are more SUMOylated compared with the wild-type protein, and this is associated with increased aggregation and inclusion formation. We detected a marked increase in PIAS2 expression along with SUMOylated α-synuclein in PD brains, providing a causal mechanism underlying the up-regulation of α-synuclein SUMOylation in the disease. We also found a significant proportion of Lewy bodies in nigral neurons containing SUMO1 and PIAS2. Our observations suggest that SUMOylation of α-synuclein by PIAS2 promotes α-synuclein aggregation by two mutually reinforcing mechanisms. First, it has a direct proaggregatory effect on α-synuclein. Second, SUMOylation facilitates α-synuclein aggregation by blocking its ubiquitin-dependent degradation pathways and promoting its accumulation. Therefore, inhibitors of α-synuclein SUMOylation provide a strategy to reduce α-synuclein levels and possibly aggregation in PD.
NEDD4
Synuclein
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Protein ubiquitination is of great cellular importance through its central role in processes such as degradation, DNA repair, endocytosis and inflammation. Canonical ubiquitination takes place on lysine residues, but in the past 15 years non-lysine ubiquitination on serine, threonine and cysteine has been firmly established. With the emerging importance of non-lysine ubiquitination, it is crucial to identify the responsible molecular machinery and understand the mechanistic basis for non-lysine ubiquitination. Here, we first provide an overview of the literature that has documented non-lysine ubiquitination. Informed by these examples, we then discuss the molecular mechanisms and cellular implications of non-lysine ubiquitination, and conclude by outlining open questions and future perspectives in the field.
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RNF4
SUMO enzymes
Deubiquitinating enzyme
Ubiquitin-conjugating enzyme
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Immunoprecipitation
SUMO enzymes
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Transcriptional activity
SUMO enzymes
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SUMO enzymes
Ubiquitin-Protein Ligases
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