Series 06 December 2023

Translation and protein quality control

Our understanding of the complex regulation of protein synthesis and its integration with other steps of gene expression such as mRNA decay has dramatically increased. Furthermore, we are gaining important insights into the quality-control mechanisms that ensure the correct co-translational folding of proteins and their targeting to specific cell compartments. In this series of Reviews we focus on the mechanisms that control translation, protein quality control and related cellular processes, and reveal how their deregulation affects ageing and diseases such as cancer, neurodegeneration and infectious diseases.

Reviews

The molecular basis of translation initiation and its regulation in eukaryotes

Translation is controlled mainly during its initiation. Recent studies in yeast and mammals provide new insights into the mechanism of translation initiation regulation in health and in various diseases, and open avenues for the development of innovative therapies targeting the translation machinery.
- Jailson Brito Querido
- Irene Díaz-López
- V. Ramakrishnan
Review Article5 Dec 2023 Nature Reviews Molecular Cell Biology
Molecular mechanisms underlying nucleotide repeat expansion disorders

Expansion of short tandem repeats can impair RNA and protein function and cause diseases through four main mechanisms: transcription repression, RNA gelation and sequestration of RNA-binding proteins, protein gain of function, and repeat-associated non-AUG toxic translation. Synergy between these mechanisms exacerbates disease, but also offers promising therapeutic targets.
- Indranil Malik
- Chase P. Kelley
- Peter K. Todd
Review Article17 Jun 2021 Nature Reviews Molecular Cell Biology
Intracellular mRNA transport and localized translation

High-resolution imaging technologies have revealed that all living organisms localize mRNAs in subcellular compartments, creating translation hotspots that locally tune gene expression. Insight has been gained into the mechanisms of mRNA transport and local mRNA translation, including into the role of messenger ribonucleoproteins and higher-order RNA granules in these processes.
- Sulagna Das
- Maria Vera
- Evelina Tutucci
Review Article9 Apr 2021 Nature Reviews Molecular Cell Biology
Mechanisms and regulation of protein synthesis in mitochondria

The majority of mitochondrial proteins are encoded in the nucleus, but mitochondria have an independent protein synthesis machinery that is required for the biogenesis of the respiratory chain. Recent insights into the mechanisms and regulation of mitochondrial protein synthesis have increased our understanding of mitochondrial function and its integration with cell physiology.
- Eva Kummer
- Nenad Ban
Review Article16 Feb 2021 Nature Reviews Molecular Cell Biology
Quality control of the mitochondrial proteome

The mitochondrial proteome comprises ~1,000–1,500 nuclear-encoded and mitochondrial-encoded proteins. To ensure proper mitochondrial function, cells use multiple mechanisms of quality control that survey mitochondrial protein biogenesis, import and folding, and allow mitochondria to adapt to the changing needs as well as to respond to stresses that compromise proteostasis.
- Jiyao Song
- Johannes M. Herrmann
- Thomas Becker
Review Article22 Oct 2020 Nature Reviews Molecular Cell Biology
Mechanisms, regulation and functions of the unfolded protein response

The unfolded protein response (UPR) comprises a network of signalling pathways that reprogramme transcription, translation and protein modifications to relieve the load of unfolded or misfolded proteins in the endoplasmic reticulum lumen and restore proteostasis. Understanding the regulation of the UPR and the role it has in the pathophysiology of various cell types and organs might open new therapeutic avenues.
- Claudio Hetz
- Kezhong Zhang
- Randal J. Kaufman
Review Article26 May 2020 Nature Reviews Molecular Cell Biology
Ribosome assembly coming into focus

Our understanding of eukaryotic ribosome assembly has been boosted by recently published cryo-electron microscopy structures of yeast ribosome assembly intermediates. These studies highlight the roles of RNA compaction, checkpoints and proofreading mechanisms of pre-ribosomal particles in the nucleolus, nucleus and cytoplasm.
- Sebastian Klinge
- John L. Woolford Jr
Review Article22 Nov 2018 Nature Reviews Molecular Cell Biology
Translation deregulation in human disease

Translation deregulation causes many human diseases, which can be broadly categorized into tRNA or ribosomal dysfunction, and deregulation of the integrated stress response or the mTOR pathway. The complexity of the translation process and its cellular contexts could explain the phenotypic variability of these disorders.
- Soroush Tahmasebi
- Arkady Khoutorsky
- Nahum Sonenberg
Review Article23 Jul 2018 Nature Reviews Molecular Cell Biology
Regulation of proteasome assembly and activity in health and disease

Protein degradation by the proteasome is crucial for the control of many cellular processes, and defects in proteasomal degradation may lead to cancer and neurodegeneration. TOR complex 1 has a key role in regulating proteasome abundance and assembly and in integrating proteasomal activity with autophagy pathways and, more generally, cell physiology.
- Adrien Rousseau
- Anne Bertolotti
Review Article31 Jul 2018 Nature Reviews Molecular Cell Biology
Roadblocks and resolutions in eukaryotic translation

Ribosomes encounter obstacles during translation elongation that cause their stalling and can have a profound impact on protein yield. Ribosome stalling depends on the genetic code, amino acid availability, regulatory elements and mRNA context and can be resolved by resumption of translation or by ribosome rescue and recycling.
- Anthony P. Schuller
- Rachel Green
Review Article14 May 2018 Nature Reviews Molecular Cell Biology
Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Structures in 5′ untranslated regions of eukaryotic mRNAs contribute to gene regulation by controlling cap-dependent and cap-independent translation initiation through diverse mechanisms. New structure probing technologies coupled with techniques such as compensatory mutagenesis will likely identify new structured RNA elements and help elucidate their function.
- Kathrin Leppek
- Rhiju Das
- Maria Barna
Review Article22 Nov 2017 Nature Reviews Molecular Cell Biology
Codon optimality, bias and usage in translation and mRNA decay

The uneven use of the synonymous amino acid codons in the transcriptome coupled with the relative concentrations of different tRNA species gives rise to non-uniform codon decoding rates by ribosomes, known as codon optimality. Codon optimality influences translation efficiency and fidelity, protein folding and mRNA decay.
- Gavin Hanson
- Jeff Coller
Review Article11 Oct 2017 Nature Reviews Molecular Cell Biology

Translation and protein quality control

Reviews

The molecular basis of translation initiation and its regulation in eukaryotes

Molecular mechanisms underlying nucleotide repeat expansion disorders

Intracellular mRNA transport and localized translation

Mechanisms and regulation of protein synthesis in mitochondria

Quality control of the mitochondrial proteome

Mechanisms, regulation and functions of the unfolded protein response

Ribosome assembly coming into focus

Translation deregulation in human disease

Regulation of proteasome assembly and activity in health and disease

Roadblocks and resolutions in eukaryotic translation

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Codon optimality, bias and usage in translation and mRNA decay

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