GIGA 2021 Annual Report 59 SELECTED PUBLICATIONS ERG transcription factors have a splicing regulatory function involving RBFOX2 that is altered in the EWS-FLI1 oncogenic fusion.Saulnier O, Guedri-Idjouadiene K, Aynaud MM, Chakraborty A, Bruyr J, Pineau J, O’Grady T, Mirabeau O, Grossetête S, Galvan B, Claes M, Al Oula Hassoun Z, Sadacca B, Laud K, Zaïdi S, Surdez D, Baulande S, Rambout X, Tirode F, Dutertre M, Delattre O, Dequiedt F. Nucleic Acids Res. 2021 May 21;49(9):5038-5056. The HTLV-1 viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape. Vandermeulen C, O’Grady T, Wayet J, Galvan B, Maseko S, Cherkaoui M, Desbuleux A, Coppin G, Olivet J, Ben Ameur L, Kataoka K, Ogawa S, Hermine O, Marcais A, Thiry M, Mortreux F, Calderwood MA, Van Weyenbergh J, Peloponese JM, Charloteaux B, Van den Broeke A, Hill DE, Vidal M, Dequiedt F, Twizere JC. PLoS Pathog. 2021 Sep 20;17(9):e1009919. Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27. Pillaiyar T, Rosato F, Wozniak M, Blavier J, Charles M, Laschet C, Kronenberger T, Müller CE, Hanson J. Eur J Med Chem. 2021 Dec 5;225:113777. The phosphoinositide 5-phosphatase INPP5K: From gene structure to in vivo functions. Schurmans S, Vande Catsyne CA, Desmet C, Moës B. Adv Biol Regul. 2021 Jan;79:100760. THE HTLV-1 VIRAL ONCOPROTEINS TAX AND HBZ REPROGRAM THE CELLULAR MRNA SPLICING LANDSCAPE Splicing events, producing multiple mRNA and protein isoforms, participate in proteome and transcriptome diversity in eukaryotes. The importance of mRNA splicing is illustrated by the observation that splicing programs are often altered in cancer cells to produce cancer-specific transcripts that are translated into divergent protein isoformsparticipatinginoncogenicprocesses.Inthecontextofinfectious diseases, it is also well known that viruses exploit the host splicing machinery to compensate for their small genomes and expand the viral proteome. However, there is limited understanding of the direct or indirect effects of viral products in regulating host RNA splicing. In a collaborative study, including national (Unit of Animal Genomics at GIGA) and international (Dana-Farber Cancer Institute and Harvard Medical School from the US, Université Montpellier and Université de Lyon) researchers from the Laboratory of Viral Interactomes led by Dr Twizere, examined how Tax and HBZ, two key effector oncogenic proteins of the human T-cell leukemia virus type 1 (HTLV-1) highjack the splicing machinery of the infected cell. Infection by HTLV-I induces an oncogenic processes that culminate in a T-cell neoplasm, known as Adult T cell leukemia/lymphoma (ATLL). The authors found that in addition to inducing massive changes in gene expression levels, Tax and HBZ perturb the splicing landscape by altering cassette exons in opposing manners, with Tax predominantly inducing exon inclusion while HBZ induces exon exclusion. Interestingly, the effects of Tax and HBZ on the cellular transcriptome is acheived via their direct interaction with a large number of host transcription and splicing factors. While some of these host interactors are shared by both Tax and HBZ, many are also specific for either viral proteins. By comparing their results with data obtained from independent cohorts of Japanese and Afro-Caribbean patients, the researchers identified common splicing changes that might represent clinically useful biomarkers for ATLL. Information about specific splicing isoforms induced by Tax and/or HBZ will be beneficial to our understanding of ATLL biology, including perturbation of metabolic pathways. The HTLV-1 viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape. Vandermeulen C, O’Grady T, Wayet J, Galvan B, Maseko S, Cherkaoui M, Desbuleux A, Coppin G, Olivet J, Ben Ameur L, Kataoka K, Ogawa S, Hermine O, Marcais A, Thiry M, Mortreux F, Calderwood MA, Van Weyenbergh J, Peloponese JM, Charloteaux B, Van den Broeke A, Hill DE, Vidal M, Dequiedt F, Twizere JC. PLoS Pathog. 2021 Sep 20;17(9):e1009919.
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