bims-proteo Biomed News
on Proteostasis
Issue of 2023–12–10
sixteen papers selected by
Eric Chevet, INSERM
  1. The generation of detergent-insoluble clipped fragments from an ERAD substrate in mammalian cells.
  2. UVRAG: orchestrating the initiation of reticulophagy.
  3. ER chaperones use a protein folding and quality control glyco-code.
  4. Insights into the ISG15 transfer cascade by the UBE1L activating enzyme.
  5. Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth.
  6. A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ.
  7. Hsf1 and the molecular chaperone Hsp90 support a 'rewiring stress response' leading to an adaptive cell size increase in chronic stress.
  8. Spatial regulation of DNA damage tolerance protein Rad5 interconnects genome stability maintenance and proteostasis networks.
  9. Structure and mechanism of the human CTDNEP1-NEP1R1 membrane protein phosphatase complex necessary to maintain ER membrane morphology.
  10. Complete set of the Atg8-E1-E2-E3 conjugation machinery forms an interaction web that mediates membrane shaping.
  11. An Arabidopsis Rab18 GTPase promotes autophagy by tethering ATG18a to the ER in response to nutrient starvation.
  12. Subdomain dynamics enable chemical chain reactions in non-ribosomal peptide synthetases.
  13. The integrated stress response signaling during the persistent HIV infection.
  14. Cancer Evolution: A Multifaceted Affair.
  15. TXNDC12 inhibits lipid peroxidation and ferroptosis.
  16. The molecular basis of translation initiation and its regulation in eukaryotes.
  1. Sci Rep. 2023 Dec 06. 13(1): 21508
    The generation of detergent-insoluble clipped fragments from an ERAD substrate in mammalian cells.
    Grant J Daskivich, Jeffrey L Brodsky.
      Proteostasis ensures the proper synthesis, folding, and trafficking of proteins and is required for cellular and organellar homeostasis. This network also oversees protein quality control within the cell and prevents accumulation of aberrant proteins, which can lead to cellular dysfunction and disease. For example, protein aggregates irreversibly disrupt proteostasis and can exert gain-of-function toxic effects. Although this process has been examined in detail for cytosolic proteins, how endoplasmic reticulum (ER)-tethered, aggregation-prone proteins are handled is ill-defined. To determine how a membrane protein with a cytoplasmic aggregation-prone domain is routed for ER-associated degradation (ERAD), we analyzed a new model substrate, TM-Ubc9ts. In yeast, we previously showed that TM-Ubc9ts ERAD requires Hsp104, which is absent in higher cells. In transient and stable HEK293 cells, we now report that TM-Ubc9ts degradation is largely proteasome-dependent, especially at elevated temperatures. In contrast to yeast, clipped TM-Ubc9ts polypeptides, which are stabilized upon proteasome inhibition, accumulate and are insoluble at elevated temperatures. TM-Ubc9ts cleavage is independent of the intramembrane protease RHBDL4, which clips other classes of ERAD substrates. These studies highlight an unappreciated mechanism underlying the degradation of aggregation-prone substrates in the ER and invite further work on other proteases that contribute to ERAD.
    DOI:  https://doi.org/10.1038/s41598-023-48769-z
  2. Autophagy. 2023 Dec 06.
    UVRAG: orchestrating the initiation of reticulophagy.
    Xuehong Qian, Jiajia Sun, Yixian Cui.
      Reticulophagy is a selective autophagy of the endoplasmic reticulum (ER) mediated by cargo receptors. It plays a crucial role in ER quality control, yet the mechanisms that initiate reticulophagy remain poorly understood. Our study identified the multifunctional protein UVRAG (UV radiation resistance associated gene) as a novel regulator of reticulophagy. UVRAG interacts with sheet and tubular reticulophagy receptors, regulates the oligomerization of receptors and facilitates their interaction with LC3/GABARAP, critical for ER fragmentation and autophagosome targeting. Remarkably, we found that UVRAG's function in reticulophagy initiation is independent of its traditional role in macroautophagy. Furthermore, UVRAG enhances the degradation of ER-associated mutant proteins linked to diseases like diabetes. Our findings offer insights into the mechanisms of reticulophagy initiation and highlight UVRAG's therapeutic potential in ER-related diseases.
    Keywords:  Autophagy; LC3/GABARAP; UVRAG; cargo receptor; reticulophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2291937
  3. Mol Cell. 2023 Nov 30. pii: S1097-2765(23)00922-X. [Epub ahead of print]
    ER chaperones use a protein folding and quality control glyco-code.
    Kevin P Guay, Haiping Ke, Nathan P Canniff, Gracie T George, Stephen J Eyles, Malaiyalam Mariappan, Joseph N Contessa, Anne Gershenson, Lila M Gierasch, Daniel N Hebert.
      N-glycans act as quality control tags by recruiting lectin chaperones to assist protein maturation in the endoplasmic reticulum. The location and composition of N-glycans (glyco-code) are key to the chaperone-selection process. Serpins, a class of serine protease inhibitors, fold non-sequentially to achieve metastable active states. Here, the role of the glyco-code in assuring successful maturation and quality control of two human serpins, alpha-1 antitrypsin (AAT) and antithrombin III (ATIII), is described. We find that AAT, which has glycans near its N terminus, is assisted by early lectin chaperone binding. In contrast, ATIII, which has more C-terminal glycans, is initially helped by BiP and then later by lectin chaperones mediated by UGGT reglucosylation. UGGT action is increased for misfolding-prone disease variants, and these clients are preferentially glucosylated on their most C-terminal glycan. Our study illustrates how serpins utilize N-glycan presence, position, and composition to direct their proper folding, quality control, and trafficking.
    Keywords:  ER-mediated protein quality control; ERQC; N-linked glycosylation; endoplasmic reticulum; lectin chaperones; protein folding; protein homeostasis; protein maturation; proteostasis; serpins
    DOI:  https://doi.org/10.1016/j.molcel.2023.11.006
  4. Nat Commun. 2023 Dec 02. 14(1): 7970
    Insights into the ISG15 transfer cascade by the UBE1L activating enzyme.
    Iona Wallace, Kheewoong Baek, J Rajan Prabu, Ronnald Vollrath, Susanne von Gronau, Brenda A Schulman, Kirby N Swatek.
      The attachment of the ubiquitin-like protein ISG15 to substrates by specific E1-E2-E3 enzymes is a well-established signalling mechanism of the innate immune response. Here, we present a 3.45 Å cryo-EM structure of a chemically trapped UBE1L-UBE2L6 complex bound to activated ISG15. This structure reveals the details of the first steps of ISG15 recognition and UBE2L6 recruitment by UBE1L (also known as UBA7). Taking advantage of viral effector proteins from severe acute respiratory coronavirus 2 (SARS-CoV-2) and influenza B virus (IBV), we validate the structure and confirm the importance of the ISG15 C-terminal ubiquitin-like domain in the adenylation reaction. Moreover, biochemical characterization of the UBE1L-ISG15 and UBE1L-UBE2L6 interactions enables the design of ISG15 and UBE2L6 mutants with altered selectively for the ISG15 and ubiquitin conjugation pathways. Together, our study helps to define the molecular basis of these interactions and the specificity determinants that ensure the fidelity of ISG15 signalling during the antiviral response.
    DOI:  https://doi.org/10.1038/s41467-023-43711-3
  5. Cell Chem Biol. 2023 Nov 30. pii: S2451-9456(23)00421-X. [Epub ahead of print]
    Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth.
    Yvonne T Kschonsak, Xinxin Gao, Stephen E Miller, Sunhee Hwang, Hadir Marei, Ping Wu, Yanjie Li, Karen Ruiz, Kristel Dorighi, Loryn Holokai, Pirunthan Perampalam, Wen-Ting K Tsai, Yee-Seir Kee, Nicholas J Agard, Seth F Harris, Rami N Hannoush, Felipe de Sousa E Melo.
      Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate limiting to realize the full clinical potential of regenerative medicine. Focusing on the Wnt pathway, here we describe a series of disulfide-constrained peptides (DCPs) that promote Wnt signaling activity by modulating the cell surface levels of ZNRF3, an E3 ubiquitin ligase that controls the abundance of the Wnt receptor complex FZD/LRP at the plasma membrane. Mechanistically, monomeric DCPs induce ZNRF3 ubiquitination, leading to its cell surface clearance, ultimately resulting in FZD stabilization. Furthermore, we engineered multimeric DCPs that induce expansive growth of human intestinal organoids, revealing a dependence between valency and ZNRF3 clearance. Our work highlights a strategy for the development of potent, biologically active Wnt signaling pathway agonists via targeting of ZNRF3.
    Keywords:  Wnt signaling; cystine-knot peptide; disulfide-constrained peptide; membrane bound E3 ubiquitin ligase; tissue regeneration
    DOI:  https://doi.org/10.1016/j.chembiol.2023.11.006
  6. Nat Commun. 2023 Dec 04. 14(1): 8016
    A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ.
    Andrew J Tao, Jiewei Jiang, Gillian E Gadbois, Pavitra Goyal, Bridget T Boyle, Elizabeth J Mumby, Samuel A Myers, Justin G English, Fleur M Ferguson.
      Understanding how small molecules bind to specific protein complexes in living cells is critical to understanding their mechanism-of-action. Unbiased chemical biology strategies for direct readout of protein interactome remodelling by small molecules would provide advantages over target-focused approaches, including the ability to detect previously unknown ligand targets and complexes. However, there are few current methods for unbiased profiling of small molecule interactomes. To address this, we envisioned a technology that would combine the sensitivity and live-cell compatibility of proximity labelling coupled to mass spectrometry, with the specificity and unbiased nature of chemoproteomics. In this manuscript, we describe the BioTAC system, a small-molecule guided proximity labelling platform that can rapidly identify both direct and complexed small molecule binding proteins. We benchmark the system against µMap, photoaffinity labelling, affinity purification coupled to mass spectrometry and proximity labelling coupled to mass spectrometry datasets. We also apply the BioTAC system to provide interactome maps of Trametinib and analogues. The BioTAC system overcomes a limitation of current approaches and supports identification of both inhibitor bound and molecular glue bound complexes.
    DOI:  https://doi.org/10.1038/s41467-023-43507-5
  7. Elife. 2023 Dec 07. pii: RP88658. [Epub ahead of print]12
    Hsf1 and the molecular chaperone Hsp90 support a 'rewiring stress response' leading to an adaptive cell size increase in chronic stress.
    Samarpan Maiti, Kaushik Bhattacharya, Diana Wider, Dina Hany, Olesya Panasenko, Lilia Bernasconi, Nicolas Hulo, Didier Picard.
      Cells are exposed to a wide variety of internal and external stresses. Although many studies have focused on cellular responses to acute and severe stresses, little is known about how cellular systems adapt to sublethal chronic stresses. Using mammalian cells in culture, we discovered that they adapt to chronic mild stresses of up to two weeks, notably proteotoxic stresses such as heat, by increasing their size and translation, thereby scaling the amount of total protein. These adaptations render them more resilient to persistent and subsequent stresses. We demonstrate that Hsf1, well known for its role in acute stress responses, is required for the cell size increase, and that the molecular chaperone Hsp90 is essential for coupling the cell size increase to augmented translation. We term this translational reprogramming the 'rewiring stress response', and propose that this protective process of chronic stress adaptation contributes to the increase in size as cells get older, and that its failure promotes aging.
    Keywords:  aging; cell biology; cytoplasmic density; human; proteostasis; senescence; stress adaptation; translation
    DOI:  https://doi.org/10.7554/eLife.88658
  8. Nucleic Acids Res. 2023 Dec 06. pii: gkad1176. [Epub ahead of print]
    Spatial regulation of DNA damage tolerance protein Rad5 interconnects genome stability maintenance and proteostasis networks.
    Carl P Lehmann, Paula González-Fernández, José Antonio Tercero.
      The Rad5/HLTF protein has a central role in the tolerance to DNA damage by mediating an error-free mode of bypassing unrepaired DNA lesions, and is therefore critical for the maintenance of genome stability. We show in this work that, following cellular stress, Rad5 is regulated by relocalization into two types of nuclear foci that coexist within the same cell, which we termed 'S' and 'I'. Rad5 S-foci form in response to genotoxic stress and are associated with Rad5's function in maintaining genome stability, whereas I-foci form in the presence of proteotoxic stress and are related to Rad5's own proteostasis. Rad5 accumulates into S-foci at DNA damage tolerance sites by liquid-liquid phase separation, while I-foci constitute sites of chaperone-mediated sequestration of Rad5 at the intranuclear quality control compartment (INQ). Relocalization of Rad5 into each type of foci involves different pathways and recruitment mechanisms, but in both cases is driven by the evolutionarily conserved E2 ubiquitin-conjugating enzyme Rad6. This coordinated differential relocalization of Rad5 interconnects DNA damage response and proteostasis networks, highlighting the importance of studying these homeostasis mechanisms in tandem. Spatial regulation of Rad5 under cellular stress conditions thus provides a useful biological model to study cellular homeostasis as a whole.
    DOI:  https://doi.org/10.1093/nar/gkad1176
  9. bioRxiv. 2023 Nov 20. pii: 2023.11.20.567952. [Epub ahead of print]
    Structure and mechanism of the human CTDNEP1-NEP1R1 membrane protein phosphatase complex necessary to maintain ER membrane morphology.
    Shujuan Gao, Jake W Carrasquillo Rodríguez, Shirin Bahmanyar, Michael V Airola.
      C-terminal Domain Nuclear Envelope Phosphatase 1 (CTDNEP1) is a non-canonical protein serine/threonine phosphatase that regulates ER membrane biogenesis. Inactivating mutations in CTDNEP1 correlate with development of medulloblastoma, an aggressive childhood cancer. The transmembrane protein Nuclear Envelope Phosphatase 1 Regulatory Subunit 1 (NEP1R1) binds CTDNEP1, but the molecular details by which NEP1R1 regulates CTDNEP1 function are unclear. Here, we find that knockdown of CTDNEP1 or NEP1R1 in human cells generate identical phenotypes, establishing CTDNEP1-NEP1R1 as an evolutionarily conserved membrane protein phosphatase complex that restricts ER expansion. Mechanistically, NEP1R1 acts as an activating regulatory subunit that directly binds and increases the phosphatase activity of CTDNEP1. By defining a minimal NEP1R1 domain sufficient to activate CTDNEP1, we determine high resolution crystal structures of the CTDNEP1-NEP1R1 complex bound to a pseudo-substrate. Structurally, NEP1R1 engages CTDNEP1 at a site distant from the active site to stabilize and allosterically activate CTDNEP1. Substrate recognition is facilitated by a conserved Arg residue that binds and orients the substrate peptide in the active site. Together, this reveals mechanisms for how NEP1R1 regulates CTDNEP1 and explains how cancer-associated mutations inactivate CTDNEP1.
    DOI:  https://doi.org/10.1101/2023.11.20.567952
  10. Nat Struct Mol Biol. 2023 Dec 06.
    Complete set of the Atg8-E1-E2-E3 conjugation machinery forms an interaction web that mediates membrane shaping.
    Jahangir Md Alam, Tatsuro Maruyama, Daisuke Noshiro, Chika Kakuta, Tetsuya Kotani, Hitoshi Nakatogawa, Nobuo N Noda.
      Atg8, a ubiquitin-like protein, is conjugated with phosphatidylethanolamine (PE) via Atg7 (E1), Atg3 (E2) and Atg12-Atg5-Atg16 (E3) enzymatic cascade and mediates autophagy. However, its molecular roles in autophagosome formation are still unclear. Here we show that Saccharomyces cerevisiae Atg8-PE and E1-E2-E3 enzymes together construct a stable, mobile membrane scaffold. The complete scaffold formation induces an in-bud in prolate-shaped giant liposomes, transforming their morphology into one reminiscent of isolation membranes before sealing. In addition to their enzymatic roles in Atg8 lipidation, all three proteins contribute nonenzymatically to membrane scaffolding and shaping. Nuclear magnetic resonance analyses revealed that Atg8, E1, E2 and E3 together form an interaction web through multivalent weak interactions, where the intrinsically disordered regions in Atg3 play a central role. These data suggest that all six Atg proteins in the Atg8 conjugation machinery control membrane shaping during autophagosome formation.
    DOI:  https://doi.org/10.1038/s41594-023-01132-2
  11. Dev Cell. 2023 Nov 24. pii: S1534-5807(23)00582-8. [Epub ahead of print]
    An Arabidopsis Rab18 GTPase promotes autophagy by tethering ATG18a to the ER in response to nutrient starvation.
    Jiaqi Sun, Yang Shao, Songyang Wang, Xunzheng Li, Shuqing Feng, Weina Wang, Pierre Leroy, Chengyang Li, Huanquan Zheng.
      The expansion of autophagosomes requires a controlled association with the endoplasmic reticulum (ER). However, the mechanisms governing this process are not well defined. In plants, ATG18a plays a key role in autophagosome formation in response to stress, yet the factors regulating the process are unknown. This study finds that ATG18a acts as a downstream effector of RABC1, a member of the poorly characterized Rab18/RabC GTPase subclass in plants. Active RABC1 interacts with ATG18a on the ER, particularly under nutrient starvation. In rabc1 mutants, autophagy is compromised, especially under nutrient deprivation, affecting the ER association and expansion of ATG18a-positive autophagosomes. Furthermore, both dominant-negative and constitutively active RABC1 forms inhibit autophagy. The dominant inactive RABC1 impedes the ER association of ATG18a, whereas the constitutively active RABC1 delays ATG18a detachment from the ER. Collectively, RABC1 regulates the ER association and the subsequent detachment of ATG18a-positive autophagosomes during nutrient starvation.
    Keywords:  ATG18a; RABC1; Rab18; autophagosomes; autophagy; endoplasmic reticulum; plant stress responses; small Rab GTPase
    DOI:  https://doi.org/10.1016/j.devcel.2023.11.006
  12. Nat Chem. 2023 Dec 04.
    Subdomain dynamics enable chemical chain reactions in non-ribosomal peptide synthetases.
    Xun Sun, Jonas Alfermann, Hao Li, Maxwell B Watkins, Yi-Tsao Chen, Thomas E Morrell, Florian Mayerthaler, Chia-Ying Wang, Tamiki Komatsuzaki, Jhih-Wei Chu, Nozomi Ando, Henning D Mootz, Haw Yang.
      Many peptide-derived natural products are produced by non-ribosomal peptide synthetases (NRPSs) in an assembly-line fashion. Each amino acid is coupled to a designated peptidyl carrier protein (PCP) through two distinct reactions catalysed sequentially by the single active site of the adenylation domain (A-domain). Accumulating evidence suggests that large-amplitude structural changes occur in different NRPS states; yet how these molecular machines orchestrate such biochemical sequences has remained elusive. Here, using single-molecule Förster resonance energy transfer, we show that the A-domain of gramicidin S synthetase I adopts structurally extended and functionally obligatory conformations for alternating between adenylation and thioester-formation structures during enzymatic cycles. Complementary biochemical, computational and small-angle X-ray scattering studies reveal interconversion among these three conformations as intrinsic and hierarchical where intra-A-domain organizations propagate to remodel inter-A-PCP didomain configurations during catalysis. The tight kinetic coupling between structural transitions and enzymatic transformations is quantified, and how the gramicidin S synthetase I A-domain utilizes its inherent conformational dynamics to drive directional biosynthesis with a flexibly linked PCP domain is revealed.
    DOI:  https://doi.org/10.1038/s41557-023-01361-4
  13. iScience. 2023 Dec 15. 26(12): 108418
    The integrated stress response signaling during the persistent HIV infection.
    Erica A Mendes, Yuyang Tang, Guochun Jiang.
      Human immunodeficiency virus-1 (HIV) infection is a chronic disease under antiretroviral therapy (ART), during which active HIV replication is effectively suppressed. Stable viral reservoirs are established early in infection and cannot be eradicated in people with HIV (PWH) by ART alone, which features residual immune inflammation with disease-associated secondary comorbidities. Mammalian cells are equipped with integrated stress response (ISR) machinery to detect intrinsic and extrinsic stresses such as heme deficiency, nutrient fluctuation, the accumulation of unfolded proteins, and viral infection. ISR is the part of the innate immunity that defends against pathogen infection or environmental alteration, thereby maintaining homeostasis to avoid diseases. Here, we describe how this machinery responds to the off-target effects of ART and persistent HIV infection in both the peripheral compartments and the brain. The latter may be important for us to better understand the mechanisms of stable HIV reservoirs and HIV-associated neurocognitive disorders.
    Keywords:  Cell biology; Virology
    DOI:  https://doi.org/10.1016/j.isci.2023.108418
  14. Cancer Discov. 2023 Dec 06. OF1-OF13
    Cancer Evolution: A Multifaceted Affair.
    Giovanni Ciriello, Luca Magnani, Sarah J Aitken, Leila Akkari, Sam Behjati, Douglas Hanahan, Dan A Landau, Nuria Lopez-Bigas, Darío G Lupiáñez, Jean-Christophe Marine, Ana Martin-Villalba, Gioacchino Natoli, Anna C Obenauf, Elisa Oricchio, Paola Scaffidi, Andrea Sottoriva, Alexander Swarbrick, Giovanni Tonon, Sakari Vanharanta, Johannes Zuber.
      Cancer cells adapt and survive through the acquisition and selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based on heritable genetic changes has provided insights into the mechanisms supporting cancer evolution. However, cancer hallmarks also emerge via heritable nongenetic mechanisms, including epigenetic and chromatin topological changes, and interactions between tumor cells and the tumor microenvironment. Recent findings on tumor evolutionary mechanisms draw a multifaceted picture where heterogeneous forces interact and influence each other while shaping tumor progression. A comprehensive characterization of the cancer evolutionary toolkit is required to improve personalized medicine and biomarker discovery.
    SIGNIFICANCE: Tumor evolution is fueled by multiple enabling mechanisms. Importantly, genetic instability, epigenetic reprogramming, and interactions with the tumor microenvironment are neither alternative nor independent evolutionary mechanisms. As demonstrated by findings highlighted in this perspective, experimental and theoretical approaches must account for multiple evolutionary mechanisms and their interactions to ultimately understand, predict, and steer tumor evolution.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0530
  15. iScience. 2023 Dec 15. 26(12): 108393
    TXNDC12 inhibits lipid peroxidation and ferroptosis.
    Lanlan Tang, Yan Yu, Wenjun Deng, Jiao Liu, Yichun Wang, Fanghua Ye, Rui Kang, Daolin Tang, Qingnan He.
      Ferroptosis is a type of regulated cell death characterized by lipid peroxidation and subsequent damage to the plasma membrane. Here, we report a ferroptosis resistance mechanism involving the upregulation of TXNDC12, a thioredoxin domain-containing protein located in the endoplasmic reticulum. The inducible expression of TXNDC12 during ferroptosis in leukemia cells is inhibited by the knockdown of the transcription factor ATF4, rather than NFE2L2. Mechanistically, TXNDC12 acts to inhibit lipid peroxidation without affecting iron accumulation during ferroptosis. When TXNDC12 is overexpressed, it restores the sensitivity of ATF4-knockdown cells to ferroptosis. Moreover, TXNDC12 plays a GPX4-independent role in inhibiting lipid peroxidation. The absence of TXNDC12 enhances the tumor-suppressive effects of ferroptosis induction in both cell culture and animal models. Collectively, these findings demonstrate an endoplasmic reticulum-based anti-ferroptosis pathway in cancer cells with potential translational applications.
    Keywords:  Biochemistry; Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.108393
  16. Nat Rev Mol Cell Biol. 2023 Dec 05.
    The molecular basis of translation initiation and its regulation in eukaryotes.
    Jailson Brito Querido, Irene Díaz-López, V Ramakrishnan.
      The regulation of gene expression is fundamental for life. Whereas the role of transcriptional regulation of gene expression has been studied for several decades, it has been clear over the past two decades that post-transcriptional regulation of gene expression, of which translation regulation is a major part, can be equally important. Translation can be divided into four main stages: initiation, elongation, termination and ribosome recycling. Translation is controlled mainly during its initiation, a process which culminates in a ribosome positioned with an initiator tRNA over the start codon and, thus, ready to begin elongation of the protein chain. mRNA translation has emerged as a powerful tool for the development of innovative therapies, yet the detailed mechanisms underlying the complex process of initiation remain unclear. Recent studies in yeast and mammals have started to shed light on some previously unclear aspects of this process. In this Review, we discuss the current state of knowledge on eukaryotic translation initiation and its regulation in health and disease. Specifically, we focus on recent advances in understanding the processes involved in assembling the 43S pre-initiation complex and its recruitment by the cap-binding complex eukaryotic translation initiation factor 4F (eIF4F) at the 5' end of mRNA. In addition, we discuss recent insights into ribosome scanning along the 5' untranslated region of mRNA and selection of the start codon, which culminates in joining of the 60S large subunit and formation of the 80S initiation complex.
    DOI:  https://doi.org/10.1038/s41580-023-00624-9
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