SUMO-activating enzyme subunit 1 and subunit 2 (SAE1-SAE2)

The SUMO-activating enzyme subunit 1 and subunit 2 (SAE1-SAE2) complex is a heterodimeric E1 enzyme that catalyzes the first and rate-limiting step of the SUMOylation pathway [2, 9]. This post-translational modification involves the ATP-dependent activation of Small Ubiquitin-like Modifier (SUMO) proteins and their subsequent attachment to target proteins, thereby regulating critical cellular processes such as DNA repair, nuclear transport, and cell cycle progression [2, 12]. SAE1-SAE2 is frequently overexpressed in various cancers, particularly those driven by the MYC oncogene, where it supports tumor cell survival and facilitates evasion of the innate immune system [4, 6, 14]. Therapeutic targeting of the SAE1-SAE2 complex, most notably with the small-molecule inhibitor subasumstat (TAK-981), aims to disrupt the SUMOylation cascade to induce apoptosis and stimulate a potent Type I interferon-mediated antitumor immune response [1, 3, 7]. Beyond oncology, the complex is implicated in inflammatory conditions like rheumatoid arthritis and is often hijacked by viruses to suppress host immune defenses [9, 10]. As a therapeutic target, SAE1-SAE2 offers a novel approach to treating aggressive malignancies by exploiting the 'SUMO addiction' of cancer cells while simultaneously enhancing the body's innate immune activity [2, 6, 13].

Other names

SUMO-activating enzyme (SAE)SUMO E1 activating enzymeAOS1/UBA2 complexSUMO1-activating enzyme subunit 1 and Ubiquitin-like modifier-activating enzyme 2Sentrin-activating enzyme

Inhibition of the SUMO-activating enzyme complex, which prevents the ATP-dependent activation of SUMO proteins and their subsequent covalent conjugation to target lysine residues on substrate proteins [1, 2, 3].