The SPPL3-Defined Glycosphingolipid Repertoire Orchestrates HLA Class I-Mediated Immune Responses.
The SPPL3-Defined Glycosphingolipid Repertoire Orchestrates HLA Class I-Mediated Immune Responses.
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DOI：
10.1016/j.immuni.2020.11.003
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发表时间：
2021-01-12
期刊：
影响因子：
32.4
通讯作者：
Spaapen RM
中科院分区：
文献类型：
--
作者：
Jongsma MLM;de Waard AA;Raaben M;Zhang T;Cabukusta B;Platzer R;Blomen VA;Xagara A;Verkerk T;Bliss S;Kong X;Gerke C;Janssen L;Stickel E;Holst S;Plomp R;Mulder A;Ferrone S;Claas FHJ;Heemskerk MHM;Griffioen M;Halenius A;Overkleeft H;Huppa JB;Wuhrer M;Brummelkamp TR;Neefjes J;Spaapen RM
HLA I类（HLA-I）糖蛋白通过将抗原呈递给同源CD 8 + T细胞来驱动免疫应答。这一过程经常被肿瘤和病原体劫持，用于免疫逃避。由于恢复HLA-I抗原呈递的选择是有限的，我们的目的是确定可药物化的HLA-I途径靶点。使用迭代全基因组筛选，我们发现细胞表面鞘糖脂（GSL）库决定有效的HLA-I抗原呈递。我们表明，蛋白酶SPPL 3的缺乏增强了B3 GNT 5酶活性，导致表面新乳糖系列GSL的上调。这些GSL在空间上阻碍抗体和受体与HLA-I的相互作用，并减少CD 8 + T细胞活化。此外，胶质瘤中SPPL 3-B3 GNT 5通路紊乱与患者生存率降低相关。我们表明，免疫调节作用可以通过使用临床批准的药物抑制GSL合成来逆转。总的来说，我们的研究确定了一个GSL签名，抑制免疫识别，并代表了癌症，感染和自身免疫的潜在治疗靶点。许多鞘糖脂（GSL）在细胞表面表达;然而，它们的功能仍然是未知的。Jongsma等人鉴定蛋白酶SPPL 3破坏GSL合成酶B3 GNT 5，其GSL产物负面影响HLA-I介导的免疫应答。该途径代表了癌症、感染和自身免疫的潜在治疗靶点。
HLA class I (HLA-I) glycoproteins drive immune responses by presenting antigens to cognate CD8+ T cells. This process is often hijacked by tumors and pathogens for immune evasion. Because options for restoring HLA-I antigen presentation are limited, we aimed to identify druggable HLA-I pathway targets. Using iterative genome-wide screens, we uncovered that the cell surface glycosphingolipid (GSL) repertoire determines effective HLA-I antigen presentation. We show that absence of the protease SPPL3 augmented B3GNT5 enzyme activity, resulting in upregulation of surface neolacto-series GSLs. These GSLs sterically impeded antibody and receptor interactions with HLA-I and diminished CD8+ T cell activation. Furthermore, a disturbed SPPL3-B3GNT5 pathway in glioma correlated with decreased patient survival. We show that the immunomodulatory effect could be reversed through GSL synthesis inhibition using clinically approved drugs. Overall, our study identifies a GSL signature that inhibits immune recognition and represents a potential therapeutic target in cancer, infection, and autoimmunity. Numerous glycosphingolipids (GSLs) are expressed at the cell surface; however, their functions remain mostly unknown. Jongsma et al. identify that the protease SPPL3 destroys the GSL synthesis enzyme B3GNT5, whose GSL products negatively affect HLA-I-mediated immune responses. This pathway represents a potential therapeutic target in cancer, infection, and autoimmunity.
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影响因子：
32.4
作者：
Dersh D;Phelan JD;Gumina ME;Wang B;Arbuckle JH;Holly J;Kishton RJ;Markowitz TE;Seedhom MO;Fridlyand N;Wright GW;Huang DW;Ceribelli M;Thomas CJ;Lack JB;Restifo NP;Kristie TM;Staudt LM;Yewdell JW
通讯作者：
Yewdell JW
影响因子：
5.4
作者：
Achdout, Hagit;Manaster, Irit;Mandelboim, Ofer
通讯作者：
Mandelboim, Ofer
影响因子：
56.9
作者：
Blomen, Vincent A.;Majek, Peter;Brummelkamp, Thijn R.
通讯作者：
Brummelkamp, Thijn R.
影响因子：
3.8
作者：
Anaya, Jordan
通讯作者：
Anaya, Jordan
影响因子：
15.3
作者：
BARBOSA, JA;SANTOSAGUADO, J;BIRO, PA
通讯作者：
BIRO, PA