SUMO, a small ubiquitin-related modifier, is known to covalently attach to a number of nuclear regulatory proteins such as p53, I B, promyelocytic leukemia protein and c-Jun. The sumoylation reaction is catalyzed by the SUMO protease, which exposes the Cterminal active glycine residue of the nascent SUMO, the heterodimeric SUMO activating enzyme, the SUMO conjugating enzyme, Ubc9, and SUMO protein ligases, in a manner similar to ubiquitinylation. Identification of SUMO-regulated proteins is hampered by the fact that many sumoylated proteins are present at a level below normal detection limit. This limitation was overcome by either in vivo overexpression of Myc-SUMO or in vitro sumoylation with excess biotin-SUMO and Ubc9. Sumoylated proteins so obtained were affinity purified or isolated by immunoprecipitation. The isolated sumoylated proteins were identified by sequence analysis using mass spectrometric methods. Results reveal that several heterogeneous nuclear ribonucleoproteins (hnRNPs), zinc finger proteins, and nuclear pore complex proteins were sumoylated. The sumoylation of hnRNP A1, hnRNP F, and hnRNP K were confirmed in vivo by coimmunoprecipitation. In view of the facts that hnRNPs have been implicated in RNA splicing, transport, stability, and translation, our findings suggest that sumoylation could play an important role in regulating mRNA metabolism.R eversible covalent modification of proteins is a widely used regulatory mechanism for transmitting biological signals and for regulating the activity, biosynthesis, and degradation of major enzymes. This is due, in part, to its enormous capacity for integrating biological information and for signal amplification (1, 2). In addition to modification with low molecular weight modifiers, such as phosphorylation, nucleotidylation, and acetylation, ubiquitin is a well documented posttranslational protein modifier. Ubiquitinylation involves the covalent attachment of the C terminus of ubiquitin to the -amino moiety of a specific lysyl residue in modified proteins. In general, polyubiquitinylation tends to associate with the 26 S proteasome-mediated protein degradation, whereas monoubiquitinylation has been reported to be involved in receptor endocytosis, protein sorting, subnuclear trafficking, meiosis, and chromatin remodeling (3-5). To date, there are Ͼ10 known ubiquitin-like proteins that have been shown to ligate to other target protein molecules. Among them, small ubiquitin-related modifier (SUMO) is the most studied modifier. It possesses only an 18% identity in sequence homology to ubiquitin; nevertheless, its 3D structure is very similar to that of ubiquitin. SUMO has been shown to ligate to numerous proteins and modulate their translocation, activity, or stability (6-9). In view of the fact that, in mammalian cells, there are two more SUMO homologs, SUMO2 and SUMO3, additional functions of protein sumoylation have yet to be identified.Similar to ubiquitinylation, covalent attachment of SUMO to its target proteins requires three or four enzymes, namel...
Conjugation of the small ubiquitin-like modifier (SUMO) to target proteins regulates numerous biological processes and has been implicated in tumorigenesis and metastasis. The three SUMO isoforms in vertebrates, SUMO1 and the highly similar SUMO2 and SUMO3, can be conjugated to unique as well as overlapping subsets of target proteins. Yet, it is still not clear whether roles for each family member are distinct or whether redundancy exists. Here we describe a mutant mouse line that completely lacks SUMO1, but surprisingly is viable and lacks any overt phenotype. Our study points to compensatory utilization of SUMO2 and/or SUMO3 for sumoylation of SUMO1 targets. The ability of SUMO isoforms to substitute for one another has important implications for rational targeting of the SUMO pathway.
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