Measles virus induces expression of SIP110, a constitutively membrane clustered lipid phosphatase, which inhibits T cell proliferation.
Interference of measles virus (MV) with phosphatidyl-inositol-3-kinase (PI3K) activation in response to T cell receptor ligation was identified as important for the induction of T cell paralysis. We now show that MV exposure of unstimulated T cells induces expression of SIP110, an isoform of the lipid phosphatase SHIP145, which is translated from an intron-derived sequences containing mRNA. We found that MV contact can regulate stimulated exon inclusion into pre-mRNAs by targeting PI3K or MAPK-dependent nuclear translocation and activation of splicing regulatory serine-arginine rich (SR) and Sam68 proteins. Induction of SIP110 in resting T cells relied on MV-dependent interference with basal activity of the PI3K. SIP110 was cloned from MV-exposed T cells, and, when transiently expressed in primary or Jurkat T cells, localized into membrane clusters independently of T cell activation. Confirming that SIP110 is a catalytically active lipid phosphatase, its transgenic expression abolished basal and impaired PMA/ionomycin-stimulated phosphorylation of the Akt kinase which is important for T cell proliferation. Thus MV causes induction of SIP110 expression, which constitutively depletes the cellular phosphoinositol-3,4,5-phosphate pool suggesting that thereby the threshold for activation signals necessary for the induction of T cell proliferation is raised.
Avota
Elita
E
Institute for Virology and Immunobiology, University of Wuerzburg, Versbacher Str. 7, D-97078 Wuerzburg, Germany.
Harms
Harry
H
Schneider-Schaulies
Sibylle
S
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D008459:Measles virus / Q000254:growth & development*; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism / Q000821:virology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014709:Vero Cells
D018960:Hyaluronan Receptors; D015759:Ionomycin; D007476:Ionophores; D008563:Membrane Lipids; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols; D010744:Phosphoric Monoester Hydrolases; D013755:Tetradecanoylphorbol Acetate; C118303:phosphoinositide-3,4,5-triphosphate