Wobble tRNA modification and hydrophilic amino acid patterns dictate protein fate.

Amino Acids/chemistry/genetics/metabolism; Cell Line, Tumor; Codon Usage; Gene Knockdown Techniques; Humans; Hydrophobic and Hydrophilic Interactions; Multienzyme Complexes/genetics/metabolism; Peptide Chain Elongation, Translational; Protein Aggregates/genetics; Proteolysis; Proteomics; RNA Processing, Post-Transcriptional; RNA, Messenger/metabolism; RNA, Transfer/genetics/metabolism; Uridine/metabolism

Abstract :

[en] Regulation of mRNA translation elongation impacts nascent protein synthesis and integrity and plays a critical role in disease establishment. Here, we investigate features linking regulation of codon-dependent translation elongation to protein expression and homeostasis. Using knockdown models of enzymes that catalyze the mcm(5)s(2) wobble uridine tRNA modification (U(34)-enzymes), we show that gene codon content is necessary but not sufficient to predict protein fate. While translation defects upon perturbation of U(34)-enzymes are strictly dependent on codon content, the consequences on protein output are determined by other features. Specific hydrophilic motifs cause protein aggregation and degradation upon codon-dependent translation elongation defects. Accordingly, the combination of codon content and the presence of hydrophilic motifs define the proteome whose maintenance relies on U(34)-tRNA modification. Together, these results uncover the mechanism linking wobble tRNA modification to mRNA translation and aggregation to maintain proteome homeostasis.

Research center :

GIGA‐R - Giga‐Research - ULiège

Disciplines :

Oncology
Biochemistry, biophysics & molecular biology

Author, co-author :

Rapino, Francesca ^✱; Université de Liège - ULiège > GIGA Stem Cells - Cancer Signaling

ZHOU, ZHAOLI ^✱

RONCERO SANCHEZ, Ana Maria ^✱

Joiret, Marc ; Université de Liège - ULiège > GIGA In silico medecine - Biomechanics Research Unit

Seca, Christian ; Université de Liège - ULiège > GIGA Stem Cells - Cancer Signaling

El Hachem, Najla ; Université de Liège - ULiège > GIGA Stem Cells - Cancer Signaling

Valenti, Gianluca ; Université de Liège - ULiège > Département de langues et littératures romanes > Langue et littérature italiennes

Latini, Sara

Shostak, Kateryna ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale

Geris, Liesbet ; Université de Liège - ULiège > Département d'aérospatiale et mécanique > Génie biomécanique

More authors (8 more)

^✱ These authors have contributed equally to this work.

Language :

English

Title :

Wobble tRNA modification and hydrophilic amino acid patterns dictate protein fate.

Publication date :

2021

Journal title :

Nature Communications

eISSN :

2041-1723

Publisher :

Nature Publishing Group, United Kingdom

Volume :

Issue :

Pages :

2170

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Fondation contre le Cancer [BE]
WELBIO - Walloon Excellence in Life Sciences and Biotechnology [BE]
ULiège - Université de Liège [BE]

Available on ORBi :

since 04 May 2021

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