Studies of mutations of assembly factor Hit 1 in budding yeast suggest translation defects as the molecular basis for PEHO syndrome.
Fiche publication
Date publication
juillet 2022
Journal
The Journal of biological chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MOTORINE Iouri, Dr MARCHAND Virginie
Tous les auteurs :
Dreggors-Walker RE, Cohen LN, Khoshnevis S, Marchand V, Motorin Y, Ghalei H
Lien Pubmed
Résumé
Regulation of protein synthesis is critical for control of gene expression in all cells. Ribosomes are ribonucleoprotein machines responsible for translating cellular proteins. Defects in ribosome production, function or regulation are detrimental to the cell and cause human diseases, such as progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome. PEHO syndrome is a devastating neurodevelopmental disorder caused by mutations in the ZNHIT3 gene, which encodes an evolutionarily conserved nuclear protein. The precise mechanisms by which ZNHIT3 mutations lead to PEHO syndrome are currently unclear. Studies of the ZNHIT3 homolog in budding yeast (Hit1) revealed that this protein is critical for formation of small nucleolar ribonucleoprotein complexes (snoRNPs) that are required for rRNA processing and 2'-O-methylation. Here, we use budding yeast as a model system to reveal the basis for the molecular pathogenesis of PEHO syndrome. We show that missense mutations modeling those found in PEHO syndrome patients cause a decrease in steady-state Hit1 protein levels, a significant reduction of box C/D snoRNA levels, and subsequent defects in rRNA processing and altered cellular translation. Using RiboMethSeq analysis of rRNAs isolated from actively translating ribosomes, we reveal site-specific changes in the rRNA modification pattern of PEHO syndrome mutant yeast cells. Our data suggest that PEHO syndrome is a ribosomopathy and reveal potential new aspects of the molecular basis of this disease in translation dysregulation.
Mots clés
Hit1, PEHO syndrome, ZNHIT3, assembly factor, rRNA methylation, rRNA modification, rRNA processing, ribosome assembly, ribosomopathy, small nucleolar RNA (snoRNA), small nucleolar ribonucleoprotein (snoRNP), zinc finger HIT protein
Référence
J Biol Chem. 2022 07 14;:102261