checkpoints/quality control steps in the pre-40S particle maturation pathway. A very recent review provides a complementary view to ours on small subunit biogenesis in yeast (Chaker-Margot, 2018). 2 | PRE-40S PARTICLE MATURATION IN SACCHAROMYCES CEREVISIAE 2.1 | Maturation pathway of pre-40S particles in S. cerevisiaeThe first precursor to the small ribosomal subunit is termed the small subunit (SSU) processome, also referred to as the 90S pre-ribosomal particle. It is formed by the co-transcriptional assembly of most of the small subunit ribosomal proteins (RPSs), AFs, and small nucleolar ribonucleoprotein particles (snoRNPs) on the nascent pre-rRNA transcript. The assembly and structure of this fascinating entity has been reviewed recently (Barandun, Hunziker, & Klinge, 2018) and will not be discussed further here. We will mostly concentrate on the maturation steps that follow the disassembly of the SSU processome, which leads to the release of the first pre-40S particle that contains the 20S pre-rRNA. This RNA species is generated by endonucleolytic cleavages of the RNA polymerase I transcript at sites A1, the 5 0 end of 18S rRNA and A2, within internal transcribed spacer 1 (ITS1). 20S pre-rRNA thus encompasses the 18S rRNA flanked at its 3 0 extremity by a 211-nucleotide-long fragment of ITS1. To yield the mature 40S ribosomal subunit, the evolving pre-40S particle undergoes maturation steps in the nucleus and the cytoplasm that include RNA conformational rearrangements, stabilization of RP integration, elimination of the ITS1 fragment, and removal of all AFs.The first pre-40S particle generated following disassembly of the SSU processome contains, in addition to the 20S pre-rRNA, the following AFs that have been recruited during formation of the SSU processome: Enp1p, the endonuclease Nob1p and its partner Pno1p/Dim2p, the methyltransferase Dim1p, and probably the helicase Prp43p. These AFs are then joined in the nucleus by Ltv1p, the kinase Hrr25p, the ATPase/kinase Rio2p, and the GTPase-like protein Tsr1p. The potential roles of these AFs in the maturation process and their dissociation stage will be discussed below. Of particular note is the fact that Nob1p is the endonuclease responsible for the cleavage at the 3 0 end of the 18S rRNA sequence (termed site D) that eliminates the ITS1 fragment and thus releases 18S rRNA. Nob1p is required for D-site cleavage in vivo and is able on its own to specifically perform this cleavage on a naked in vitro-transcribed RNA substrate (Fatica,

Ribosome biogenesis lies at the nexus of various signaling pathways coordinating protein synthesis with cell growth and proliferation. This process is regulated by well-described transcriptional mechanisms, but a growing body of evidence indicates that other levels of regulation exist. Here we show that the Ras/mitogen-activated protein kinase (MAPK) pathway stimulates post-transcriptional stages of human ribosome synthesis. We identify RIOK2, a pre-40S particle assembly factor, as a new target of the MAPK-activated kinase RSK. RIOK2 phosphorylation by RSK stimulates cytoplasmic maturation of late pre-40S particles, which is required for optimal protein synthesis and cell proliferation. RIOK2 phosphorylation facilitates its release from pre-40S particles and its nuclear re-import, prior to completion of small ribosomal subunits. Our results bring a detailed mechanistic link between the Ras/MAPK pathway and the maturation of human pre-40S particles, which open a hitherto poorly explored area of ribosome biogenesis.