Phosphor-IWS1-dependent U2AF2 splicing regulates trafficking of CAR-E-positive intronless gene mRNAs and sensitivity to viral infection

Georgios I Laliotis; Adam D Kenney; Evangelia Chavdoula; Arturo Orlacchio; Abdul Kaba; Alessandro La Ferlita; Vollter Anastas; Christos Tsatsanis; Joal D Beane; Lalit Sehgal; Vincenzo Coppola; Jacob S Yount; Philip N Tsichlis

doi:10.1038/s42003-021-02668-z

Phosphor-IWS1-dependent U2AF2 splicing regulates trafficking of CAR-E-positive intronless gene mRNAs and sensitivity to viral infection

Commun Biol. 2021 Oct 11;4(1):1179. doi: 10.1038/s42003-021-02668-z.

Authors

Georgios I Laliotis^{1

2

3

4}, Adam D Kenney^{5

6}, Evangelia Chavdoula^{7

5}, Arturo Orlacchio^{7

5}, Abdul Kaba⁷, Alessandro La Ferlita^{7

5

8}, Vollter Anastas^{7

5

9}, Christos Tsatsanis^{10

11}, Joal D Beane^{5

12}, Lalit Sehgal^{5

13}, Vincenzo Coppola^{7

5}, Jacob S Yount^{5

6}, Philip N Tsichlis^{14

15

16}

Affiliations

¹ Department of Cancer Biology and Genetics, The Ohio State University College of Medicine Columbus, Columbus, OH, 43210, USA. glaliot1@jhmi.edu.
² The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA. glaliot1@jhmi.edu.
³ University of Crete, School of Medicine, Heraklion Crete, 71500, Greece. glaliot1@jhmi.edu.
⁴ Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. glaliot1@jhmi.edu.
⁵ The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA.
⁶ Department of Microbial Infection and Immunity and Infectious Diseases Institute, The Ohio State University, Columbus, OH, 43210, USA.
⁷ Department of Cancer Biology and Genetics, The Ohio State University College of Medicine Columbus, Columbus, OH, 43210, USA.
⁸ Department of Clinical and Experimental Medicine, Bioinformatics Unit, University of Catania, Catania, 95131, Italy.
⁹ Tufts Graduate School of Biomedical Sciences, Program in Genetics, Boston, MA, 02111, USA.
¹⁰ University of Crete, School of Medicine, Heraklion Crete, 71500, Greece.
¹¹ Institute of Molecular Biology and Biotechnology, Heraklion, Crete, 70013, Greece.
¹² Department of Surgery, Division of Surgical Oncology, Columbus, OH, 43210, USA.
¹³ Department of Medicine, Division of Hematology, The Ohio State University, Columbus, OH, 43210, USA.
¹⁴ Department of Cancer Biology and Genetics, The Ohio State University College of Medicine Columbus, Columbus, OH, 43210, USA. Philip.tsichlis@osumc.edu.
¹⁵ The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA. Philip.tsichlis@osumc.edu.
¹⁶ Tufts Graduate School of Biomedical Sciences, Program in Genetics, Boston, MA, 02111, USA. Philip.tsichlis@osumc.edu.

Abstract

AKT-phosphorylated IWS1 promotes Histone H3K36 trimethylation and alternative RNA splicing of target genes, including the U2AF65 splicing factor-encoding U2AF2. The predominant U2AF2 transcript, upon IWS1 phosphorylation block, lacks the RS-domain-encoding exon 2, and encodes a protein which fails to bind Prp19. Here we show that although both U2AF65 isoforms bind intronless mRNAs containing cytoplasmic accumulation region elements (CAR-E), only the RS domain-containing U2AF65 recruits Prp19 and promotes their nuclear export. The loading of U2AF65 to CAR-Elements was RS domain-independent, but RNA PolII-dependent. Virus- or poly(I:C)-induced type I IFNs are encoded by genes targeted by the pathway. IWS1 phosphorylation-deficient cells therefore, express reduced levels of IFNα1/IFNβ1 proteins, and exhibit enhanced sensitivity to infection by multiple cytolytic viruses. Enhanced sensitivity of IWS1-deficient cells to Vesicular Stomatitis Virus and Reovirus resulted in enhanced apoptotic cell death via caspase activation. Inhibition of this pathway may therefore sensitize cancer cells to oncolytic viruses.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Retracted Publication

Abstract

Publication types

Grants and funding