Wednesday, 12th December 2018

 Virology and Microbiology

    mRNA structure and translation control in biological systems

 

 


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Iván Ventoso

 

BSciStaff

 

BPublications

 

 

 

 

Research summary:

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Stress-induced eIF2 phosphorylation leads to a general attenuation of mRNA translation (or translatome). However, for a small subset of mRNAs, translation continues or is even induced during stress response. This translational reprogramming is promoted by some alternative initiation factors such as eIF2A, whose exact role in this process is being investigated in our lab. Some Alphavirus mRNA can efficiently translate under these conditions by the presence of specific RNA structures (stem-loops) that probably have counterparts in some  stress-induced cellular mRNA. 


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A model for the function of DLP structures (downstream stem loop) in translation of some viral mRNAs. By placing on the solvent side of 40S ribosome (gray), DLP structure stalls the advance of 40S ribosome in a way that allows the placement of initiation codon of mRNA on the P site of ribosome to initiate translation.

fig03.300px
An evolutionary scenario to explain how Alphaviruses could evolve in the past to expand their host range. As the antiviral PKR-eIF2 pathway is only present in vertebrates, the acquisition of DLP structures may have allowed early Alphaviruses to colonize vertebrates and the subsequent geographic spreading. Nowadays, Alphaviral mRNA translation can use an eIF2-dependent translation when replicating in insects and an eIF2-independent mechanism for replication in vertebrates that requires the DLP structure.

 

To ensure survival and adaptation, living organisms must respond properly to endogenous and environmental stresses. We study how mammalian cells respond to stress by adapting the translation efficiency of mRNAs (translatome), trying to identify those structural elements in mRNA and initiation factors (eIFs) that promote the differential translation of specific mRNAs during stress. We are also studying how some viruses have evolved to adapt translation of their mRNA to stress conditions in infected cell and tissues, a useful model that allows us to extract valuable information on the functioning of stress and antiviral responses in mammals. This also allows us a better understanding of dynamic interactions between virus and host that regulate important aspects such as evolution, tropism, pathogenesis, and geographic spreading of the viruses. We work with two models:

•  Infection of cultured cells and animals with Arbovirus (eg. Sindbis).

•  The unfolded protein response (UPR) in murine cells and animals.

We combine biochemistry, molecular genetics, structural analysis of RNA and high-throughput techniques (translatomics), together with bioinformatics and systems biology approaches to address these topics to an extent that could allow us to make predictions about the physiological response of these systems.

 


 

Main contributions:

Ventoso I (2012). Adaptive changes in alphavirus mRNA translation allowed colonization of vertebrate hosts. J. Virol. 86 (17): 9484-94.

Ventoso I, Kochetov A, Montaner D, Dopazo J  and Santoyo J (2012). Extensive translatome remodeling during RE stress response in mammalian cells. Plos One 7(5): e35915.

Toribio R & Ventoso I (2010). Inhibition of host translation by virus infection in vivo. Proc Natl Acad Sci U S A. 107: 9837-42.

Ventoso I, Sanz MA, Molina S, Berlanga JJ, Carrasco L, and Esteban M (2006). Translational resistance of late alfavirus mRNA to eIF2a phosphorylation: a strategy to overcome the antiviral effect of protein kinase PKR. Genes Dev. 20: 87-100.

Ventoso I, Blanco R, Perales C, Carrasco L (2001). HIV-1 protease cleaves eukaryotic initiation factor 4G and inhibits cap-dependent translation. Proc Natl Acad Sci U S A. 98(23): 12966-71.

 


 

Thesis

René Toribio López. Cambios Traduccionales que regulan la interacción virus hospedador. Implicación en el desarrollo de virus oncolíticos. Dpto. Biología Molecular. UAM 2010. Sobresaliente Cum Laude

 

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