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1. Combination of hydrophobicity and codon usage bias determines sorting of model K + channel protein to either mitochondria or endoplasmic reticulum.

Author

Engel AJ, Paech S, Langhans M, van Etten JL, Moroni A, Thiel G, and Rauh O

Subjects
Animals, Mitochondria metabolism, Protein Transport, Endoplasmic Reticulum metabolism, Codon metabolism, Hydrophobic and Hydrophilic Interactions, Mammals genetics, Mammals metabolism, Codon Usage, Proteins metabolism
Abstract

When the K + channel-like protein Kesv from Ectocarpus siliculosus virus 1 is heterologously expressed in mammalian cells, it is sorted to the mitochondria. This targeting can be redirected to the endoplasmic reticulum (ER) by altering the codon usage in distinct regions of the gene or by inserting a triplet of hydrophobic amino acids (AAs) into the protein's C-terminal transmembrane domain (ct-TMD). Systematic variations in the flavor of the inserted AAs and/or its codon usage show that a positive charge in the inserted AA triplet alone serves as strong signal for mitochondria sorting. In cases of neutral AA triplets, mitochondria sorting are favored by a combination of hydrophilic AAs and rarely used codons; sorting to the ER exhibits the inverse dependency. This propensity for ER sorting is particularly high when a common codon follows a rarer one in the AA triplet; mitochondria sorting in contrast is supported by codon uniformity. Since parameters like positive charge, hydrophobic AAs, and common codons are known to facilitate elongation of nascent proteins in the ribosome the data suggest a mechanism in which local changes in elongation velocity and co-translational folding in the ct-TMD influence intracellular protein sorting., (© 2023 The Authors. Traffic published by John Wiley & Sons Ltd.)

Published
2023
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2. Translation and codon usage regulate Argonaute slicer activity to trigger small RNA biogenesis

Author

Germano Cecere, Meetali Singh, Eric Cornes, Blaise Li, Piergiuseppe Quarato, Loan Bourdon, Florent Dingli, Damarys Loew, Simone Procaccia, Mécanismes de l'Hérédité épigénétique / Mechanisms of epigenetic inheritance, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Collège doctoral [Sorbonne universités], Sorbonne Université (SU), Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie [Paris], University of Trento [Trento], Some strains were provided by the CGC, funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). This project has received funding from the Institut Pasteur, the CNRS, and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program under grant agreement No. ERC-StG- 679243. M.S. and E.C. were supported by the Pasteur-Roux-Cantarini Postdoctoral Fellowship program. P.Q. was supported by Ligue Nationale Contre le Cancer (SFB19032). F.D. and D.L. have received funding from Région Ile-de-France and Fondation pour la Recherche Médicale grants to support this study., We would like to thank all the members of the Cecere laboratory, Manish Grover, Sudarshan Gadadhar, and Angela Anderson (Life Science Editors), for the helpful discussions on the paper. We thank Micheline Fromont for her help to set up Ribosome profiling. We thank Celine Didier for technical assistance. Sequencing was performed at the Biomics centre at the Institut Pasteur. We thank the Heng-Chi Lee lab, Miska lab, Desai lab, Strome lab, Mello lab, Updike lab, and Kennedy lab for sharing strains and reagents., European Project: 679243,H2020,ERC-2015-STG,RNAEPIGEN(2016), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Collège Doctoral

Subjects
Science, Small RNAs, chemical and pharmacologic phenomena, RNA-Dependent RNA Polymerase, RNA decay, Ribosome, Catalysis, Article, Cytosol, Oogonia, Protein Biosynthesis, RNAi, Argonaute Proteins, Mutation, Animals, RNA Interference, RNA, Messenger, RNA, Small Interfering, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Codon Usage, Ribosomes, [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract

In the Caenorhabditis elegans germline, thousands of mRNAs are concomitantly expressed with antisense 22G-RNAs, which are loaded into the Argonaute CSR-1. Despite their essential functions for animal fertility and embryonic development, how CSR-1 22G-RNAs are produced remains unknown. Here, we show that CSR-1 slicer activity is primarily involved in triggering the synthesis of small RNAs on the coding sequences of germline mRNAs and post-transcriptionally regulates a fraction of targets. CSR-1-cleaved mRNAs prime the RNA-dependent RNA polymerase, EGO-1, to synthesize 22G-RNAs in phase with translating ribosomes, in contrast to other 22G-RNAs mostly synthesized in germ granules. Moreover, codon optimality and efficient translation antagonize CSR-1 slicing and 22G-RNAs biogenesis. We propose that codon usage differences encoded into mRNA sequences might be a conserved strategy in eukaryotes to regulate small RNA biogenesis and Argonaute targeting., 22G-RNAs are single-stranded antisense small RNAs that are expressed in C. elegans germline. Here the authors show that CSR-1 dependent 22G-RNAs are produced in the cytosol on mRNAs actively engaged in translation and that codon usage of an mRNA regulates the biogenesis of CSR-1 dependent 22G-RNAs.

Published
2021