Impact of sphingomyelin species with different acyl chain lengths on plasma membrane organization.

Abstract

The plasma membrane (PM) is characterized by asymmetric bilayer organization in terms of both the chemistry of lipid headgroups and the physical properties of lipid acyl chains. Sphingomyelin (SM), a major outer-leaflet lipid, has long been considered a key partner of cholesterol (Chol) in the formation of ordered membrane domains. However, mammalian cells contain multiple SM species with distinct N-acyl chains, most predominantly C16:0, C24:0, and C24:1, whose structural differences can change membrane packing, Chol distribution, and interleaflet communication. Evidence from model membranes shows that C16:0 SM interacts strongly with Chol and promotes liquid-ordered domain formation. By contrast, C24:0 SM generates thicker, potentially interdigitated bilayers, supports ordered domains with altered Chol association, and may influence coupling between two leaflets. C24:1 SM combines a very-long acyl chain with unsaturation, weakening membrane packing and suppressing macroscopic phase separation in Chol-containing membranes. Asymmetric vesicle studies further indicate that C24 SM can affect Chol transbilayer partitioning, which could have consequences for Chol accessibility and homeostatic signaling. Cellular studies further indicate that remodeling SM species can alter glycosylphosphatidylinositol (GPI)-anchored protein clustering, PM order, Chol-binding probe accessibility, and signaling proteins such as the insulin receptor. Together, current evidence supports a model in which SM species diversity tunes PM organization through coupled effects on lipid packing, Chol behavior, leaflet asymmetry, and protein function. Understanding these mechanisms in living cells remains an important issue for future studies.