Nascent alt-protein chemoproteomics reveals a repressor of ribosome biogenesis

Abstract

Ribosome biogenesis in eukaryotes is a highly regulated, essential cellular process. However, few repressors of ribosome biogenesis have been identified. Here, we identify and define the function of MINAS-60 (MIcroprotein that Negatively regulates ASsembly of the pre-60S ribosomal subunit), a 130-amino acid protein co-encoded with the human pre-mRNA splicing regulator and tumor suppressor protein RBM10. MINAS-60 localizes to the nucleolus, where it associates with multiple pre-60S assembly factors. Depletion of MINAS-60 increases the amount of mature 60S ribosomal subunit in the cytoplasm and, consequently, upregulates global protein synthesis and cell proliferation. Mechanistically, we show that MINAS-60 represses late-stage pre-60S assembly and export of the mature 60S ribosome subunit to the cytoplasm. Together, these results implicate MINAS-60 as a repressor of ribosome biogenesis that acts as a checkpoint for the maturation of the large subunit (LSU). More broadly, the RBM10 transcript encodes two sequence-independent proteins that inhibit cell proliferation via different molecular mechanisms, expanding existing models of multicistronic human gene functions.