Functional interplay between the endosomal sorting complexes required for transport (ESCRT) and ubiquitin system underlies the ubiquitin-dependent sorting pathway, a specific trait of eukaryotic endomembrane system. Yet, its evolutionary origin remains unclear. Here, we show that a novel UEV-Vps23 family protein, that contains UEV and Vps23 domains, mediates an ancient ESCRT and ubiquitin system interplay in Asgard archaea. The UEV binds ubiquitin with high-affinity, making the UEV-Vps23 a sensor for sorting ubiquitinated cargo. A steadiness box in the Vps23 domain undergoes ubiquitination through a eukaryotic-like Asgard E1, E2, and RING E3 cascade. The UEV-Vps23 can switch between autoinhibited and active forms, by which likely regulates the ESCRT and ubiquitin system interplay. Furthermore, the shared sequence and structural homology among the UEV-Vps23, eukaryotic Vps23 and archaeal CdvA, implying that these proteins share a common evolutionary origin. Together, this work presents evidence that the ESCRT and ubiquitin system interplay had arisen early in Asgard evolution, antedating emergence of endomembrane system in eukaryogenesis.
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