The C-terminus of Utp4, mutated in childhood cirrhosis, is essential for ribosome biogenesis

Abstract

The small subunit (SSU) processome is a large ribonucleoprotein that is required for maturation of the 18S rRNA of the ribosome. Recently, a missense mutation in the C-terminus of an SSU processome protein, Utp4/Cirhin, was reported to cause North American Indian childhood cirrhosis (NAIC). In this study, we use Saccharomyces cerevisiae as a model to investigate the role of the NAIC mutation in ribosome biogenesis. While we find that the homologous NAIC mutation does not cause growth defects or aberrant ribosome biogenesis in yeast, we show that an intact C-terminus of Utp4 is required for cell growth and maturation of the 18S and 25S rRNAs. A protein–protein interaction map of the seven-protein t-Utp subcomplex of which Utp4 is a member shows that Utp8 interacts with the C-terminus of Utp4 and that this interaction is essential for assembly of the SSU processome and for the function of Utp4 in ribosome biogenesis. Furthermore, these results allow us to propose that NAIC may be caused by dysfunctional pre-ribosome assembly due to the loss of an interaction between the C-terminus of Utp4/Cirhin and another SSU processome protein.