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Principles of Protein Group Modification by the SUMO Pathway

Final Report Summary - SUMOGROUP (Principles of Protein Group Modification by the SUMO Pathway)

The laboratory of Stefan Jentsch is specialized in studying the function of post-translational protein modification by ubiquitin family proteins. Ubiquitylation is typically a highly selective pathway in which a plethora of dedicated enzymes target individual proteins leading to a distinct functional outcome. The function of ubiquitylation is well understood and has often been studied by deletion of individual modifying enzymes or mutation of target lysines. The function of the ubiquitin-like modifier SUMO is less understood. Although SUMOylation targets roughly as many proteins as ubiquitylation, only a very small set of enzymes is responsible for protein modification in the SUMO pathway. Moreover, despite the fact that SUMO is essential, inhibiting SUMOylation of individual substrates usually does not have deleterious consequences. Previous research of the Jentsch laboratory suggested a solution to this puzzle, as SUMOylation often targets functionally linked protein groups, where SUMO modification of the several individual subunits has additive effects and functions as intermolecular glue that stabilizes protein complexes.
Initially, protein group SUMOylation was found to be important for the formation of protein assemblies that function in homologous recombination and nucleotide excision repair. In the context of SUMOGROUP the Jentsch lab was able to expand this concept by studying several additional SUMOylated protein complexes/groups with relevance for cellular regulation and of medical importance. This study identified the substrate repertoire of all known SUMO pathway enzymes, elucidated the specificity of SUMO ligases and led to the development of novel tools to study protein group modification. Moreover, the downstream effects of SUMOylation were analyzed with a special focus on pathways that act in the disassembly of modified protein complexes.
Notwithstanding the premature termination of SUMOGROUP due to the death of Stefan Jentsch, significant insights were obtained into the broad spectrum of processes involving SUMOylation. First, SUMOGROUP yielded the most comprehensive dataset of the yeast SUMOylome, including – at least for most SUMO substrates – the identification of the corresponding SUMOylation enzymes. This included identification of numerous, previously unrecognized targets of SUMOylation, some of which have been analyzed in detail.
Overall, the findings are in strong support of the SUMO group model and of SUMO functioning as a stabilizer of protein complexes. However, examples of different modes of action were found as well, and these will help to sharpen our view of cellular control by SUMO. These included examples where SUMOylation inhibits complex formation or even promotes complex disassembly. Moreover, work done in the context of SUMOGROUP indicated an involvement of SUMOylation in protein quality control, demonstrating that SUMO has an important function in general proteostasis. We have also identified several modes of action for downstream effectors of SUMOylation. This includes novel targeting mechanisms for disassembly or degradation of SUMOylated protein groups, as well as additional post-translational modifications, altering the function of a SUMOylated target. In summary, SUMOGROUP yielded a broad view on how SUMOylation affects proteins and regulates cellular processes. It has thus not only confirmed the SUMO group hypothesis, but also unraveled novel concepts for cellular control by the still enigmatic SUMO pathway.