A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation

Momoko Narita, Timo Denk, Yoshitaka Matsuo, Takato Sugiyama, Chisato Kikuguchi, Sota Ito, Nichika Sato, Toru Suzuki, Satoshi Hashimoto, Iva Machová, Petr Tesina, Roland Beckmann () and Toshifumi Inada ()
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Momoko Narita: The University of Tokyo
Timo Denk: University of Munich
Yoshitaka Matsuo: The University of Tokyo
Takato Sugiyama: Tohoku University
Chisato Kikuguchi: The University of Tokyo
Sota Ito: The University of Tokyo
Nichika Sato: The University of Tokyo
Toru Suzuki: The University of Tokyo
Satoshi Hashimoto: Tohoku University
Iva Machová: Charles University in Prague
Petr Tesina: University of Munich
Roland Beckmann: University of Munich
Toshifumi Inada: The University of Tokyo

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Translational stalling events that result in ribosome collisions induce Ribosome-associated Quality Control (RQC) in order to degrade potentially toxic truncated nascent proteins. For RQC induction, the collided ribosomes are first marked by the Hel2/ZNF598 E3 ubiquitin ligase to recruit the RQT complex for subunit dissociation. In yeast, uS10 is polyubiquitinated by Hel2, whereas eS10 is preferentially monoubiquitinated by ZNF598 in human cells for an unknown reason. Here, we characterize the ubiquitination activity of ZNF598 and its importance for human RQT-mediated subunit dissociation using the endogenous XBP1u and poly(A) translation stallers. Cryo-EM analysis of a human collided disome reveals a distinct composite interface, with substantial differences to yeast collided disomes. Biochemical analysis of collided ribosomes shows that ZNF598 forms K63-linked polyubiquitin chains on uS10, which are decisive for mammalian RQC initiation. The human RQT (hRQT) complex composed only of ASCC3, ASCC2 and TRIP4 dissociates collided ribosomes dependent on the ATPase activity of ASCC3 and the ubiquitin-binding capacity of ASCC2. The hRQT-mediated subunit dissociation requires the K63-linked polyubiquitination of uS10, while monoubiquitination of eS10 or uS10 is not sufficient. Therefore, we conclude that ZNF598 functionally marks collided mammalian ribosomes by K63-linked polyubiquitination of uS10 for the trimeric hRQT complex-mediated subunit dissociation.

Date: 2022
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DOI: 10.1038/s41467-022-34097-9

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