Cellular differentiation state modulates the mRNA export activity of SR proteins

Author:

Botti Valentina1ORCID,McNicoll François2ORCID,Steiner Michaela C.3,Richter Florian M.4ORCID,Solovyeva Anfisa2,Wegener Marius25,Schwich Oliver D.25,Poser Ina3,Zarnack Kathi5,Wittig Ilka4,Neugebauer Karla M.1ORCID,Müller-McNicoll Michaela2ORCID

Affiliation:

1. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT

2. Cluster of Excellence Macromolecular Complexes, Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Frankfurt am Main, Germany

3. Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

4. Functional Proteomics Group, Institute for Biochemistry I, Goethe University Frankfurt, Frankfurt am Main, Germany

5. Buchmann Institute for Molecular Life Sciences, Frankfurt am Main, Germany

Abstract

SR proteins function in nuclear pre-mRNA processing, mRNA export, and translation. To investigate their cellular dynamics, we developed a quantitative assay, which detects differences in nucleocytoplasmic shuttling among seven canonical SR protein family members. As expected, SRSF2 and SRSF5 shuttle poorly in HeLa cells but surprisingly display considerable shuttling in pluripotent murine P19 cells. Combining individual-resolution cross-linking and immunoprecipitation (iCLIP) and mass spectrometry, we show that elevated arginine methylation of SRSF5 and lower phosphorylation levels of cobound SRSF2 enhance shuttling of SRSF5 in P19 cells by modulating protein–protein and protein–RNA interactions. Moreover, SRSF5 is bound to pluripotency-specific transcripts such as Lin28a and Pou5f1/Oct4 in the cytoplasm. SRSF5 depletion reduces and overexpression increases their cytoplasmic mRNA levels, suggesting that enhanced mRNA export by SRSF5 is required for the expression of pluripotency factors. Remarkably, neural differentiation of P19 cells leads to dramatically reduced SRSF5 shuttling. Our findings indicate that posttranslational modification of SR proteins underlies the regulation of their mRNA export activities and distinguishes pluripotent from differentiated cells.

Funder

Deutsche Forschungsgemeinschaft

Publisher

Rockefeller University Press

Subject

Cell Biology

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