Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2010 Apr 16;285(16):11937-47. doi: 10.1074/jbc.M109.077933. Epub 2010 Feb 4.
For major histocompatibility complex class I and II molecules, the binding of specific peptide antigens is essential for assembly and trafficking and is at the center of their quality control mechanism. However, the role of lipid antigen binding in stabilization and quality control of CD1 heavy chain (HC).beta(2)-microglobulin (beta(2)m) complexes is unclear. Furthermore, the distinct trafficking and loading routes of CD1 proteins take them from mildly acidic pH in early endososmal compartments (pH 6.0) to markedly acidic pH in lysosomes (pH 5.0) and back to neutral pH of the cell surface (pH 7.4). Here, we present evidence that the stability of each CD1 HC.beta(2)m complex is determined by the distinct pH optima identical to that of the intracellular compartments in which each CD1 isoform resides. Although stable at acidic endosomal pH, complexes are only stable at cell surface pH 7.4 when bound to specific lipid antigens. The proposed model outlines a quality control program that allows lipid exchange at low endosomal pH without dissociation of the CD1 HC.beta(2)m complex and then stabilizes the antigen-loaded complex at neutral pH at the cell surface.
对于主要组织相容性复合体 I 类和 II 类分子，特定肽抗原的结合对于组装和运输至关重要，并且是其质量控制机制的核心。然而，脂质抗原结合在 CD1 重链 (HC).β2-微球蛋白 (β2m) 复合物的稳定性和质量控制中的作用尚不清楚。此外，CD1 蛋白的独特运输和加载途径使它们从早期内体区室中的轻度酸性 pH（pH 6.0）转移到溶酶体中的明显酸性 pH（pH 5.0），然后再回到细胞表面的中性 pH（pH 7.4）。在这里，我们提供的证据表明，每个 CD1 HC.β2m 复合物的稳定性取决于与每个 CD1 同工型所在的细胞内区室相同的独特 pH 最佳值。尽管在酸性内体 pH 下稳定，但只有与特定脂质抗原结合时，复合物在细胞表面的中性 pH 7.4 下才稳定。该模型概述了一个质量控制程序，该程序允许在低内体 pH 下进行脂质交换，而不会使 CD1 HC.β2m 复合物解离，然后在细胞表面的中性 pH 下稳定负载抗原的复合物。
