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.