Studies of mutations of assembly factor Hit1 in budding yeast suggest translation defects as the molecular basis for PEHO syndrome.

Abstract

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 human zinc finger HIT-type containing protein 3 homolog in budding yeast (Hit1) revealed that this protein is critical for formation of small nucleolar ribonucleoprotein complexes 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.

• Authors: R Elizabeth Dreggors-Walker, Lauren N Cohen, Sohail Khoshnevis, Virginie Marchand, Yuri Motorin, Homa Ghalei
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 298 Issue 9 Pg. 102261 (09 2022) ISSN: 1083-351X [Electronic] United States
• PMID: 35843310 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Hit1 protein, S cerevisiae
• Nuclear Proteins
• RNA, Small Nucleolar
• Ribonucleoproteins, Small Nucleolar
• Saccharomyces cerevisiae Proteins
• Transcription Factors
• ZNHIT3 protein, human

Topics

• Brain Edema (genetics)
• Humans
• Infant, Newborn
• Mutation
• Neurodegenerative Diseases (genetics)
• Nuclear Proteins (genetics)
• Optic Atrophy (genetics)
• RNA, Small Nucleolar (metabolism)
• Ribonucleoproteins, Small Nucleolar (genetics)
• Saccharomyces cerevisiae (genetics)
• Saccharomyces cerevisiae Proteins (genetics)
• Spasms, Infantile (genetics)
• Transcription Factors (genetics)