Internal initiation of translation in eukaryotic mRNAs

Research summary:

Our main interests are focused to understand the principles guiding alternative mechanisms of translation initiation in eukaryotes. This includes structural and functional analysis of non-coding regions, and identification and characterization of RNA-binding proteins (RBPs) interacting with internal ribosome entry sites (IRES). Genomic and proteomic approaches lead us to identify the network of interactions of RBPs that perform key roles on gene expression. A representative example is Gemin5, the RNA-binding protein of the SMN complex. Defects on the SMN complex cause SMA (Spinal muscular atrophy), an autosomal rare disease. This multifunctional protein performs a critical role in translation control (Fig. 1). Gemin5 harbors a bipartite non-conventional RNA-binding site (RBS1-RBS2) on its C-terminal region, while the N-terminal domain contains 14 WD repeats that mediate the interaction with the ribosome. Using a CLIP-based procedure to search for the cellular targets of the RBS1 domain we identified an internal region of Gemin5 mRNA as a hit of RBS1. Functional analysis of this hit unveiled a feedback loop with its own mRNA, counteracting the negative effect of Gemin5 on translation.

We continue our efforts to understand RNA regulatory elements with the aim to explain the coding potential of eukaryotic genomes, expanding the number of RNAs that can be translated using cap-independent mechanisms under normal conditions or cellular stress. IRESs substitute the function of the 5’ terminal cap present in conventional mRNAs, which is the anchoring point of the translation machinery. To achieve their function, distinct IRESs assemble ribonucleoprotein complexes, which include a subset of eIFs and diverse RBPs. In all cases, RNA structure and IRES function is tightly coupled. Our specific aims were the identification of of factors modulating IRES activity, the evaluation of synergism and/or interference with other factors involved in translation control, and the understanding of RNA structural constraints which are essential for its activity. Fig. 2 shows the conformational changes observed by SHAPE upon incubation of the IRES with native ribosomes. Our findings could allow the prediction of IRES-like motifs in the cellular transcriptome, as well as to infer the role of novel RBPs harboring non-conventional RBDs in translation control.


Fig. 1.


Fig. 2.


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Last nameNameLaboratoryExt.*e-mailProfessional category
Abellán PérezSalvador3094649sabellan(at)cbm.csic.esTitulado Medio de Actividades Tecn.y Prof.GP2
Francisco VelillaMª del Rosario3094649rfrancisco(at)cbm.csic.esTitulado Sup.de Actividades Técn. y Profes. GP1
Martínez SalasEncarnación3094619emartinez(at)cbm.csic.esE. Profesores de Investigación de Organismos Públicos de Investigación
Nahavandi AraghiAzadeh3094619Becario Erasmus
Ramajo AlonsoJorge3094649jramajo(at)cbm.csic.esTécnico Sup. Actividades Téc. y Profes. GP3

Relevant publications:

  • Moreno-Morcillo, M, Francisco-Velilla, R., Embarc-Buh, A., Fernandez-Chamorro, J, Ramon-Maiques, S., and Martínez-Salas, E. (2020) Structural basis for the dimerization of Gemin5 and its role in protein recruitment and translation control. Nucleic Acids Res, 48(2):788-801.
  • Francisco-Velilla R, Embarc-Buh A, Martinez-Salas E (2019) RNA-binding modes impacting on translation control: the versatile multidomain protein Gemin5. BioEssays 41(4):e1800241.
  • Fernandez-Chamorro J, Francisco-Velilla R, Ramajo J, Martinez-Salas E (2019) IRES-driven RNA localization at ER-Golgi compartment is mediated by RAB1b and ARF5. Life Sci Alliance 2(1). pii: e201800131.
  • Lozano G, Francisco-Velilla R, Martinez-Salas E (2018) Deconstructing IRES elements: an update of structural motifs and functional divergences. Open Biology 8 (11).  pii: 180155.
  • Francisco-Velilla R, Fernandez-Chamorro J, Dotu I, Martinez-Salas E (2018) The RNA landscape of the non-canonical RNA-binding domain of Gemin5 unveils a feedback loop with its own mRNA counteracting the negative effect on translation. Nucleic Acids Res 46, 7339-7353.
  • Lozano G, Francisco-Velilla R, Martinez-Salas E (2018) Ribosome-dependent conformational flexibility changes and RNA dynamics of IRES domains revealed by differential SHAPE. Sci Rep 8(1): 5545.
  • Galan A, Lozano G, Piñeiro D, Martinez-Salas E (2017) G3BP1 interacts directly with the FMDV IRES and negatively regulates translation. FEBS J 284, 3202-3217.
  • Diaz-Toledano R, Lozano G, Martínez-Salas E (2017) In-cell SHAPE uncovers dynamic interactions between the untranslated regions of the foot-and-mouth disease virus RNA. Nucleic Acids Res 45, 1416-1432.
  • Francisco-Velilla R, Fernandez-Chamorro J, Ramajo J, Martínez-Salas, E. (2016) The RNA-binding protein Gemin5 binds directly to the ribosome and regulates global translation. Nucleic Acids Res 44, 8335-8351.
  • Lozano G, Jimenez-Aparicio R, Herrero S, Martínez-Salas E (2016) Fingerprinting the junctions of RNA secondary structure by an open-paddle wheel diruthenium compound. RNA 22, 330-338.

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