DNTTIP2 coordinates RNA exosome activities to ensure fidelity of human ribosome assembly.

Abstract

The RNA exosome-associated helicase Mtr4/MTR4 (yeast/human) is recruited by adaptor proteins bearing Arch-Interacting Motifs (AIMs) to selectively degrade RNA substrates. Although the exosome targets diverse RNAs, only a few adaptors have been identified. Here, we extend the inventory of human adaptors to include a pre-tRNA splicing-ligase complex component, a spliceosome-associated factor, and DNTTIP2, a constituent of the small ribosomal subunit (40S) precursor, the 90S pre-ribosome. Structure-guided studies reveal how the DNTTIP2^AIM-docked processive exosome core and its associated distributive exonuclease EXOSC10, which contact distant sites on the 90S pre-ribosome, cooperate to degrade part of the 5'-external transcribed spacer (5'-ETS), a key RNA scaffold that coordinates early 40S assembly. By contrast, productive pre-ribosomal RNA trimming within the 90S pre-ribosome necessitates EXOSC10, which safeguards against uncontrolled processive degradation by the DNTTIP2^AIM-docked exosome core. We propose that multivalent contacts provide a mechanistic framework by which the RNA exosome coordinates its distinct enzymatic activities, ensuring selective processing and surveillance during ribonucleoprotein particle maturation.