Measles Virus Interacts with and Alters Signal Transduction in T-Cell Lipid Rafts

Abstract

By a contact-dependent surface interaction, the measles virus (MV) glycoprotein complex induces a pronounced inhibition of T-cell proliferation. We now show that MV directly interacts with glycosphingolipidenriched membrane microdomains on human primary T cells and alters recruitment and segregation of membrane proximal signaling components. Contact-dependent interference with T-cell receptor-stimulated tyrosine phosphorylation and Ca mobilization is a late event seen 24 h after MV treatment. In contrast, stimulated recruitment of pleckstrin homology domain-containing proteins such as Akt and Vav is inhibited early after MV contact, as is segregation of the activated Akt kinase from rafts. Tyrosine phosphorylation of the regulatory subunit of the phosphatidylinositol 3-kinase (PI3K), p85, is apparently normal then, yet this protein fails to partition to the lipid raft fraction, and this is associated with stable expression of its negative regulator Cbl-b. Thus, by interaction with lipid rafts, MV contact initially targets recruitment of PI3K by preventing stimulated Cbl-b degradation and activation of PI3K-dependent signaling components.

Viruses, lipid rafts and signal transduction

“…Akt is regulated by Phosphatidylinositol 3-kinase (PI3K) which can be activated by the TCR coreceptor CD28 as well as the IL-2 receptor. Both pathways have been shown to be potently inhibited in the presence of MV [52,54]. At least in the context of CD28 stimulation, this effect is exerted at the levels of lipid rafts as both Akt and the PI3K regulatory subunit p85 are prevented from translocating to lipid rafts upon CD3/CD28 stimulation in primary T cells as a result of contact with MV.…”

“…Experimentally, T cell paralysis can be induced upon incubation of T lymphocytes with MV particles where the interaction with gp results in unresponsiveness to proliferation signals for several days, yet cells do not undergo apoptosis [50,51]. It was shown that MV contact interferes with the activation of primary T cells resulting in decreased overall tyrosine phosphorylation levels as well as Ca 2+ release upon TCR stimulation [52] and that gp contact is sufficient for specifically preventing T cells from S phase entry [51]. Interestingly, this com- plex is able to affect T cell signalling upon surface contact, which is independent of the two known entry receptors CD46 and CD150 [53].…”

“…At least in the context of CD28 stimulation, this effect is exerted at the levels of lipid rafts as both Akt and the PI3K regulatory subunit p85 are prevented from translocating to lipid rafts upon CD3/CD28 stimulation in primary T cells as a result of contact with MV. The mechanisms that mediate this raft exclusion of PI3K may include the MV induced block of Cbl-b degradation, an E3 ubiquitin ligase that negatively regulates the stability of PI3K [52]. The exclusion of key molecules in the regulation of cell proliferation from raft resident signalosomes might be crucial for the MV induced block of proliferation.…”

Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes

“…It induces expression of SIP-110, which depletes the cellular PtdIns(3,4,5)P 3 pools, suggesting that the threshold for activation signals for induction of T cell proliferation is raised (52,53).…”

Role of Membrane Rafts in Viral Infection

“…Thus, measles virus infection induces an inflammatory response through alternative complement activation [205]. Measles virusinduced immnosuppression is also responsible for signal transduction alteration such as PI3K in T cell membrane rafts [206]. Tyrosine kinase-interacting protein (Tip) of lymphotropic herpesvirus saimiri (HVS) is targeted to membrane rafts in T cells and downregulates T cell receptor (TCR) and CD4 surface expression.…”