SUMMARY
Understanding how functional lipid domains in live cell membranes are generated has posed a challenge. Here, we show that transbilayer interactions are necessary for the generation of cholesteroldependent nanoclusters of GPI-anchored proteins mediated by membrane-adjacent dynamic actin filaments. We find that long saturated acyl-chains are required for forming GPI-anchor nanoclusters. Simultaneously, at the inner leaflet, long acyl-chaincontaining phosphatidylserine (PS) is necessary for transbilayer coupling. All-atom molecular dynamics simulations of asymmetric multicomponent-membrane bilayers in a mixed phase provide evidence that immobilization of long saturated acyl-chain lipids at either leaflet stabilizes cholesterol-dependent transbilayer interactions forming local domains with characteristics similar to a liquid-ordered (lo) phase. This is verified by experiments wherein immobilization of long acyl-chain lipids at one leaflet effects transbilayer interactions of corresponding lipids at the opposite leaflet. This suggests a general mechanism for the generation and stabilization of nanoscale cholesterol-dependent and actin-mediated lipid clusters in live cell membranes.
Fully synthetic, self-adjuvanting monophosphoryl lipid A–globo H conjugate elicited strong T cell-mediated immunity that could target and kill breast cancer.
α-2,9-Polysialic acid is an
important capsular polysaccharide
expressed by serotype C Neisseria meningitidis. Its
protein conjugates are current vaccines against group C meningitis.
To address some concerns about traditional protein conjugate vaccines,
a new type of fully synthetic vaccines composed of oligosialic acids
and glycolipids was explored. In this regard, α-2,9-linked di-,
tri-, tetra-, and pentasialic acids were prepared and conjugated with
monophosphoryl lipid A (MPLA). Immunological studies of the conjugates
in C57BL/6J mouse revealed that they alone elicited robust immune
responses comparable to that induced by corresponding protein conjugates
plus adjuvant, suggesting the self-adjuvanting properties of MPLA
conjugates. The elicited antibodies were mainly IgG2b and IgG2c, suggesting
T cell dependent immunities. The antisera had strong and specific
binding to α-2,9-oligosialic acids and to group C meningococcal
polysaccharide and cell, indicating the ability of antibodies to selectively
target the bacteria. The antisera also mediated strong bactericidal
activities. Structure–activity relationship analysis of the
MPLA conjugates also revealed that the immunogenicity of oligosialic
acids decreased with elongated sugar chain, but all tested MPLA conjugates
elicited robust immune responses. It is concluded that tri- and tetrasialic
acid–MPLA conjugates are worthy of further investigation as
the first fully synthetic and self-adjuvanting vaccines against group
C meningitis.
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