The study investigates the functional heterogeneity between SUMO-1 and SUMO-2/3, two small ubiquitin-like modifiers. SUMO-1 is well characterized and implicated in various cellular processes, while SUMO-2/3 have been less studied. The authors developed a specific antibody to SUMO-2/3 and found that it detects multiple SUMO-2/3-modified proteins, indicating a higher abundance of SUMO-2/3 than SUMO-1. They observed a large pool of free, non-conjugated SUMO-2/3 that could be rapidly activated by protein-damaging stimuli such as heat shock. In contrast, SUMO-1 was preferentially modified on the Ran GTPase-activating protein RanGAP1, which localizes to the nuclear pore complex (NPC). SUMO-2/3 did not significantly modify RanGAP1, suggesting that SUMO-2/3 may play a role in cellular stress responses. The study also suggests that the SUMO-2/3 pathway may be a novel class of acute and reversible stress response, distinct from the ubiquitin pathway.The study investigates the functional heterogeneity between SUMO-1 and SUMO-2/3, two small ubiquitin-like modifiers. SUMO-1 is well characterized and implicated in various cellular processes, while SUMO-2/3 have been less studied. The authors developed a specific antibody to SUMO-2/3 and found that it detects multiple SUMO-2/3-modified proteins, indicating a higher abundance of SUMO-2/3 than SUMO-1. They observed a large pool of free, non-conjugated SUMO-2/3 that could be rapidly activated by protein-damaging stimuli such as heat shock. In contrast, SUMO-1 was preferentially modified on the Ran GTPase-activating protein RanGAP1, which localizes to the nuclear pore complex (NPC). SUMO-2/3 did not significantly modify RanGAP1, suggesting that SUMO-2/3 may play a role in cellular stress responses. The study also suggests that the SUMO-2/3 pathway may be a novel class of acute and reversible stress response, distinct from the ubiquitin pathway.