SUMO2 (small ubiquitin-like modifier 2) is a critical post-translational modification protein that regulates diverse cellular processes through covalent attachment to target proteins. SUMO2 functions as part of a conjugation system requiring E1 activation (SAE1-SAE2), E2 conjugation (UBE2I), and E3 ligases for substrate specificity 1. Unlike SUMO1, SUMO2 shares 97% homology with SUMO3 and can form polymeric chains that are particularly important for protein quality control 2. The mechanism involves SUMO2 conjugation to lysine residues, which can either stabilize proteins or target them for degradation through SUMO-targeted ubiquitin ligases (STUbLs) 2. SUMO2 modifications play protective roles in disease contexts, including stabilizing NLRP3 to regulate inflammasome activation 3, protecting TDP-43 against pathological aggregation in neurodegeneration 4, and maintaining genome stability through DHX9 regulation 5. Clinically, SUMO2 dysregulation is implicated in cancer, neurodegeneration, and inflammatory diseases 1. The paralogue-specific functions of SUMO2/3 versus SUMO1 in proteostasis make it an important therapeutic target for protein misfolding diseases and cancer 2.