A distal effect of microsomal triglyceride transfer protein deficiency on the lysosomal recycling of CD1d

Abstract

Microsomal triglyceride transfer protein (MTP) is an endoplasmic reticulum (ER)-residentlipid transfer protein involved in the biosynthesis and lipid loading of apolipoprotein B. MTP was recently suggested to directly regulate the biosynthesis of the MHC I-like, lipid antigen presenting molecule CD1d, based on coprecipitation experiments and lipid loading assays. However, we found that the major impact of MTP defi ciency occurred distal to the ER and Golgi compartments. Thus, although the rates of CD1d biosynthesis, glycosylation maturation, and internalization from the cell surface were preserved, the late but essential stage of recycling from lysosome to plasma membrane was profoundly impaired. Likewise, functional experiments indicated defects of CD1d-mediated lipid presentation in the lysosome but not in the secretory pathway. These intriguing fi ndings suggest a novel, unexpected role of MTP at a late stage of CD1d traffi cking in the lysosomal compartment.

Natural Lipid Ligands Associated with Human CD1d Targeted to Different Subcellular Compartments

“…It is conceivable that secCD1d assembles and leaves the ER in a predominantly lipid-free form, but that the ER-retained version accumulates PC during the prolonged period it spends recycling between the ER and cis -Golgi: the half-life of sec CD1d is > 20 hours ((17), data not shown). There are no data to indicate how efficiently MTP catalyzes lipid loading in the ER, and in fact one view is that it catalyzes the binding of the antigenic lipid α-galactosylceramide in the endocytic pathway and not in the ER (32), which is entirely consistent with empty CD1d molecules being assembled and secreted. Alternatively, PC binding in the ER may be efficient but lipid exchange factors present in the secretory pathway after the cis -Golgi preferentially exchange sphingomyelin for PC.…”

A closer look at CD1d molecules: new horizons in studying NKT cells

“…Furthermore, the mechanisms by which glycolipids are extracted from membranes and loaded onto CD1d molecules remain to be fully understood. Although recent papers have described the role of lipid transfer proteins, such as saposin [74], microsomal lipid transfer protein [70,75] and CD1e [76], the fine details of the mechanisms that control lipid loading and presentation are still obscure.…”

“…By replacing the gene encoding CXCR6 with GFP cDNA, it has been possible to visualize liver iNKT cells and to assess their role in immunosurveillance [68]. Lastly, the use of fluorescently labelled glycolipids is proving to be a useful tool in the tracking of CD1d molecules throughout the endosomal compartments of the cell [69,70].…”

Novel insights into lipid antigen presentation

“…MTP affects CD1 molecules probably by facilitating their stabilisation with endogenous lipids. The absence of MTP might cause generation of unstable CD1 molecules more susceptible to lysosomal degradation and with reduced recycling capacity, thus explaining the observed effects on CD1d recycling from lysosomes to plasma membrane [69].…”