Reprogramming SUMO-primed ubiquitylation: opportunities in oncology and neurology

Drugs that reprogram the cellular ubiquitin-proteasome system for removal of disease-causing proteins hold great promise as a new type of pharmacology. Small ubiquitin-related modifier (SUMO)-targeted ubiquitin ligases (StUbLs) are E3 ubiquitin ligases that mediate ubiquitylation of proteins primed by modification with SUMO. The antineoplastic drugs arsenic trioxide and fulvestrant stand out as examples for leveraging a SUMOylation-ubiquitylation cascade to inactivate the oncogenic fusion proteins PML-RARα and estrogen receptor α, respectively. However, approaches harnessing the StUbL system for targeting a broader spectrum of disease-relevant proteins are missing. Recent proof-of-concept studies indicate that proximity-inducing modalities can recruit aggregation-prone proteins to the StUbL machinery, potentially mitigating the formation of neurotoxic inclusions. We review new insights on StUbL-based therapeutics and reflect perspectives of reprogramming SUMO-StUbL signaling for use in oncology and neurology.