Integrating Rio1 activities discloses its nutrient-activated network in Saccharomyces cerevisiae

Abstract

The Saccharomyces cerevisiae kinase/adenosine triphosphatase Rio1 regulates rDNA transcription and segregation, pre-rRNA processing and small ribosomal subunit maturation. Other roles are unknown. When overexpressed, human ortholog RIOK1 drives tumor growth and metastasis. Likewise, RIOK1 promotes 40S ribosomal subunit biogenesis and has not been characterized globally. We show that Rio1 manages directly and via a series of regulators, an essential signaling network at the protein, chromatin and RNA levels. Rio1 orchestrates growth and division depending on resource availability, in parallel to the nutrient-activated Tor1 kinase. To define the Rio1 network, we identified its physical interactors, profiled its target genes/transcripts, mapped its chromatin-binding sites and integrated our data with yeast’s protein–protein and protein–DNA interaction catalogs using network computation. We experimentally confirmed network components and localized Rio1 also to mitochondria and vacuoles. Via its network, Rio1 commands protein synthesis (ribosomal gene expression, assembly and activity) and turnover (26S proteasome expression), and impinges on metabolic, energy-production and cell-cycle programs. We find that Rio1 activity is conserved to humans and propose that pathological RIOK1 may fuel promiscuous transcription, ribosome production, chromosomal instability, unrestrained metabolism and proliferation; established contributors to cancer. Our study will advance the understanding of numerous processes, here revealed to depend on Rio1 activity.

System-wide analyses of the fission yeast poly(A)+ RNA interactome reveal insights into organisation and function of RNA-protein complexes

“…Rio kinases have a conserved role in rRNA maturation and were recently reported to be regulated by binding to rRNA (Knüppel et al, 2018). However, a broader role for Rio kinases in regulating nutrient-activated expression of genes has been proposed (Iacovella et al, 2018). Our data support a model where Rio kinase activity could be regulated by more diverse RNA species.…”

A kinase-dependent checkpoint prevents escape of immature ribosomes into the translating pool

“…Previous work has also established roles for Rio1 in cell division, in which it binds ribosomal DNA (rDNA) and interacts with the regulator of nucleolar silencing and telophase exit (RENT) complex and the helicase Sgs1, which both regulate rDNA silencing, the stability of the locus, and its condensation during cell segregation. Accordingly, Rio1-depleted cells have defects in these processes [52,53]. The rescue of cell viability in the absence of Rio1 by the Pno1-KKKF mutant indicates that the essential role of Rio1 is in ribosome assembly.…”

Uncovering the assembly pathway of human ribosomes and its emerging links to disease

“…Phosphorylation substrates of the RIO family kinases have long remained elusive, but human RIOK2 was recently demonstrated to phosphorylate DIMT1L in vitro (Sloan et al , ). Furthermore, both Rio1 and RIOK1 were recently found to orchestrate a network of interactions that may couple pre‐40S maturation with metabolism and cell proliferation (Iacovella et al , ).…”