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Discovery of Deoxyceramides and Diacylglycerols As Cd1b Scaffold Lipids Among Diverse Groove-Blocking Lipids of the Human CD1 System

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Discovery of Deoxyceramides and Diacylglycerols As Cd1b Scaffold Lipids Among Diverse Groove-Blocking Lipids of the Human CD1 System Discovery of deoxyceramides and diacylglycerols as CD1b scaffold lipids among diverse groove-blocking lipids of the human CD1 system Shouxiong Huanga, Tan-Yun Chenga, David C. Younga, Emilie Layrea, Cressida A. Madigana, John Shiresb, Vincenzo Cerundoloc, John D. Altmanb, and D. Branch Moodya,1 aDepartment of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; bEmory Vaccine Center, Emory School of Medicine, Atlanta, GA 30322; and cMedical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom Edited* by Peter Cresswell, Yale University School of Medicine, New Haven, CT, and approved October 17, 2011 (received for review August 10, 2011) Unlike the dominant role of one class II invariant chain peptide (CLIP) environment (7, 8). The differing pH requirements for antigen in blocking MHC class II, comparative lipidomics analysis shows that loading, combined with enrichment of endogenous lipids in the human cluster of differentiation (CD) proteins CD1a, CD1b, CD1c, secretory pathway and exogenous lipids endosomes, are coalescing and CD1d bind lipids corresponding to hundreds of diverse accurate into a two-step model of lipid antigen presentation. First, newly mass retention time values. Although most ions were observed in translated CD1 proteins, aided by the microsomal triglyceride association with several CD1 proteins, ligands binding selectively to transport protein (MTP) (9), capture endogenous self-lipids dur- one CD1 isoform allowed the study of how differing antigen- ing or after folding at neutral pH in the ER or secretory pathway. binding grooves influence lipid capture. Although the CD1b groove Second, upon reaching the endosomes by recycling or direct 3 routes, the acidic pH facilitates the unfolding or untethering of the is distinguished by its unusually large volume (2,200 Å ) and the α ′ parallel -helices that normally restrict ligand access to the groove T tunnel, the average mass of compounds eluted from CD1b was sim- (3–6). Increased groove access promotes both unloading of the ilar to that of lipids from CD1 proteins with smaller grooves. Elution initially bound endogenous lipids and subsequent capture of the of small ligands from the large CD1b groove might be explained if exogenous lipids delivered by infection, lipid transfer proteins, or IMMUNOLOGY two small lipids bind simultaneously in the groove. Crystal struc- receptor-mediated uptake (8, 10). tures indicate that all CD1 proteins can capture one antigen with its Whereas later antigen exchange events within endosomes are hydrophilic head group exposed for T-cell recognition, but CD1b extensively characterized, the early events in which newly folded structures show scaffold lipids seated below the antigen. We found CD1 proteins load self-lipids are less well understood. The folding that ligands selectively associated with CD1b lacked the hydrophilic of nascent CD1 heavy chains is thought to involve cotranslational head group that is generally needed for antigen recognition but binding of self lipids in the ER (11). This expectation is supported interferes with scaffold function. Furthermore, we identified the by experiments that detect self-diacylglycerols, monoacylglycerols, scaffolds as deoxyceramides and diacylglycerols and directly dem- and sphingolipids eluted from CD1 proteins that have ER re- onstrate a function in augmenting presentation of a small glyco- tention signals or lack endosomal recycling motifs (2, 12, 13). Some lipid antigen to T cells. Thus, unlike MHC class II, CD1 proteins of these endogenous lipids activate T cells, so are true autoantigens capture highly diverse ligands in the secretory pathway. CD1b (14). Others are more likely nonantigenic place-holding lipids that has a mechanism for presenting either two small or one large lipid, provide a hydrophobic substrate for the initial folding reactions allowing presentation of antigens with an unusually broad range and serve a groove-blocking function until antigenic exogenous of chain lengths. lipids are encountered in acidic endosomes. Therefore, whether the human CD1 family uses one or many types of place-holding lipids, or whether individual CD1 proteins bind the same or dif- antigen presentation | Mycobacterium tuberculosis | cluster of ferent lipids, is largely unknown. CD1a (1,280 Å3), CD1b (2,200 differentiation 1 Å3), CD1c (1,780 Å3), and CD1d (1,650 Å3) grooves differ in volume and the number of pockets, known as A′,F′,C′,andtheT′ ost mammals have preserved large cluster of differentiation tunnel, located at the bottom of the groove. All grooves have an F′ M1(CD1) gene families, comprised of orthologs of human and an A′ pocket, but only CD1b forms the T′ tunnel and C′ pocket CD1a, CD1b, CD1c, and CD1d antigen-presenting molecules. (15–18). These structural studies predict that each CD1 protein Each of these CD1 protein types, known as isoforms, differs in might capture somewhat distinct classes of lipids, with the strongest sequence and 3D structure, so that their heavy chains form anti- prediction being that CD1b captures lipids with long alkyl chains gen-binding grooves of differing size and shape. CD1 proteins and higher mass. initially fold in the endoplasmic reticulum (ER), exit through the After deleting transmembrane and cytoplasmic tail sequences secretory pathway, and traffic to endosomes via direct or surface needed for endosomal trafficking, we captured cellular CD1a, mechanisms that require the binding of cytoplasmic sequences to CD1b, CD1c, and CD1d complexes and eluted ligands for entry adaptor proteins (1). These subcellular trafficking pathways ex- into a newly validated comparative lipidomics platform. As con- pose nascent CD1 proteins to diverse classes of endogenous cel- trasted with conventional MS, this platform rapidly generates lular lipids in ER, Golgi, and endosomal compartments. However, lipidomes, derived from triplicate datasets generated back-to-back whether CD1 proteins, especially the less-studied group 1 CD1 under rigorously comparable conditions. Validated protocols proteins (CD1a, CD1b, and CD1c), initially capture one or many types of groove-blocking lipids is unknown. CD1 proteins might capture a dominant lipid class that is functionally equivalent with Author contributions: S.H. and D.B.M. designed research; S.H. and T.-Y.C. performed the class II invariant chain peptide (CLIP) (2), or instead broadly research; S.H., J.S., and J.D.A. contributed new reagents/analytic tools; S.H., T.-Y.C., D.C.Y., survey various endogenous lipids. E.L., C.A.M., V.C., and D.B.M. analyzed data; and S.H. and D.B.M. wrote the paper. Cellular pH strongly influences the capture and release of lipids. The authors declare no conflict of interest. In particular, CD1b and CD1d are relatively resistant to exogenous *This Direct Submission article had a prearranged editor. antigen loading at neutral pH conditions normally found in the 1To whom correspondence should be addressed. E-mail: [email protected]. – secretory pathway (3 6). They more rapidly exchange antigens at This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. pH 4–6, which is characteristic of the late endosomal or lysosomal 1073/pnas.1112969108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1112969108 PNAS Early Edition | 1of6 Downloaded by guest on September 28, 2021 measure equivalent input lipids, lack of detector saturation, broad A B Transmembrane detection of many lipid classes, and computer-based analysis with K562-Linked Linked Zippered data filters, so that comparative analyses of thousands of molecular domain deleted CD1a,CD1b β α α α CD1c,CD1d 2m 1 2 3 features in one lipidome are possible (19). We found that the CD1a CD1b CD1c CD1d B2705 CD1a CD1b CD1c leader linker Strep-tag II 8XHis 64 HLA- human CD1 system surveys hundreds of distinct endogenous lipids P β2m α1 α2 α3 B2705 that differ in polarity, in contrast to the CLIP mechanism whereby 51 HEK293-zippered leader linker αZip 2A-TAV HC one ligand dominates in the initial loading of MHC II. Contrary to 39 CD1a β2m 28 the simple predictions arising from the large volume of CD1b CD1b β α α α 2m CD1c 1 2 3 19 groove, the spectrum of cellular lipids binding selectively to CD1b 14 is dominated by ligands with relatively low mass and no hydrophilic leader βZip BSP85 6XHis head groups. These distinct chemical features suggest that such small, headless lipids might not be antigens that contact the T-cell 1 396.801 CD1a C 0.5 453.343 836.615 543.201 661.236 760.583 receptor (TCR), but instead are the long-sought scaffold lipids 0 binding to CD1b in conjunction with antigens. We identified the 4 1 760.585 836.615 CD1b 0.5 703.574 candidate scaffold lipids as deoxyceramides and diacylglycerols, 0 760.587 813.685 and demonstrate their cofactor function in antigen presentation to 1 703.574 CD1c 788.628 0.5 731.605 T cells, defining a natural cellular mechanism for presenting lipids 432.280 543.202 661.236 0 with extraordinary lipid length discrepancy. 1 813.683 CD1d 0.5 543.202 785.651 Intensity (Counts X10 ) 703.573 898.724 Results 0 1 HLA-B27 0.5 Linked and Zippered CD1 Proteins Capture Similar Lipids. Elution of 543.203 661.237 832.307 0 peptides from MHC proteins was key to understanding the dif- 400 440 480 520 560 600 640 680 720 760 800 840 880 920 fering antigen motifs for MHC I and II proteins and the discovery m/z – of groove-blocking peptides (20 22). Similarly, broad comparisons Fig. 1. Two sets of human CD1 proteins bind cellular lipids. (A) Covalently of lipids eluted from group 1 (CD1a, CD1b, CD1c) or group 2 linked molecules were constructed by linking β2m to the heavy chains of CD1 (CD1d) CD1 proteins might lead to insights into isoform-specific fl β β or HLA-B2705 molecules through a exible linker.
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