Studies of mutations of assembly factor Hit1 in budding yeast suggest translation defects as the molecular basis for PEHO syndrome.
Studies of mutations of assembly factor Hit1 in budding yeast suggest translation defects as the molecular basis for PEHO syndrome.
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DOI：
10.1016/j.jbc.2022.102261
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发表时间：
2022-09
影响因子：
4.8
通讯作者：
Ghalei, Homa
中科院分区：
文献类型：
--
作者：
Dreggors-Walker, R. Elizabeth;Cohen, Lauren N.;Khoshnevis, Sohail;Marchand, Virginie;Motorin, Yuri;Ghalei, Homa
蛋白质合成的调节对于控制所有细胞中的基因表达至关重要。核糖体是负责翻译细胞蛋白质的核糖核蛋白机器。核糖体产生、功能或调节的缺陷对细胞有害，并导致人类疾病，如进行性脑病伴水肿、心律失常和视神经萎缩（PEHO）综合征。PEHO综合征是由ZNHIT 3基因突变引起的一种破坏性神经发育障碍，该基因编码一种进化上保守的核蛋白。ZNHIT 3突变导致PEHO综合征的确切机制目前尚不清楚。对芽殖酵母中含人锌指HIT型蛋白3同源物（HIT 1）的研究表明，该蛋白对形成小核仁核糖核蛋白复合物至关重要，而小核仁核糖核蛋白复合物是rRNA加工和2′-O-甲基化所必需的。在这里，我们使用芽殖酵母作为模型系统，以揭示PEHO综合征的分子发病机制的基础。我们发现，错义突变模型中发现的PEHO综合征患者引起的稳态Hit 1蛋白水平的下降，盒C/D snoRNA水平的显着降低，随后的缺陷rRNA加工和改变细胞翻译。使用RiboMethSeq分析从活跃翻译核糖体中分离的rRNA，我们揭示了PEHO综合征突变酵母细胞rRNA修饰模式的位点特异性变化。我们的数据表明，PEHO综合征是一种核糖体病，并揭示了这种疾病在翻译失调的分子基础的潜在新方面。
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.
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在人rRNA中2'-O-ME的分析揭示了一部分部分修饰的位置，并提供了核糖体异质性的证据。
影响因子：
14.9
作者：
Krogh N;Jansson MD;Häfner SJ;Tehler D;Birkedal U;Christensen-Dalsgaard M;Lund AH;Nielsen H
通讯作者：
Nielsen H
影响因子：
7.3
作者：
Henras, Anthony K.;Plisson-Chastang, Celia;O'Donohue, Marie-Francoise;Chakraborty, Anirban;Gleizes, Pierre-Emmanuel
通讯作者：
Gleizes, Pierre-Emmanuel
影响因子：
4.8
作者：
Khoshnevis, Sohail;Dreggors, R. Elizabeth;Ghalei, Homa
通讯作者：
Ghalei, Homa
影响因子：
14.5
作者：
Anttonen, Anna-Kaisa;Laari, Anni;Lehesjoki, Anna-Elina
通讯作者：
Lehesjoki, Anna-Elina
影响因子：
11.4
作者：
BELTRAME, M;TOLLERVEY, D
通讯作者：
TOLLERVEY, D