The causes of MHC-I-opathies in cellular stress

细胞应激中 MHC-I 疾病的原因

• 批准号: 460154834
• 负责人: Professor Dr. Sebastian Springer
• 金额: --
• 依托单位: Lehrstuhl für Theoretische Biophysik - Molekulardynamik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/460154834?language=en
• 关键词: causes; MHC; opathies; cellular; stress

Major histocompatibility complex (MHC) class I molecules (termed human leukocyte antigen (HLA I in human) are essential for mounting a cytotoxic adaptive response to intracellular pathogens and tumors. The specificity of the adoptive response relies on the accurate and efficient presentation of peptide fragments from non-self (e.g., viral or neoplastic) proteins by one of each six potentially dif-ferent HLA I molecules from two equidominantly expressed alleles of HLA-A, HLA-B and HLA-C loci in each individual. Discrimination of self from non-self is safeguarded by the elimination of auto-reactive T cells. Nevertheless, a group of autoreactive diseases (e.g. ankylosing spondylitis and oth-er spondyloarthropathies, Behçet’s disease, psoriasis, birdshot chorioretinopathy) display a strong genetic link to individual HLA I alleles. Accumulation of vast genetic data over the last four decades has recently lead to classification of those autoreactive diseases as MHC-I-opathies. Interestingly, in diseased individuals, disease-related CD8+ T cell responses to specific peptide-HLA I complexes have not been detected. This suggests that there are additional immune mechanisms (e.g innate response from NK cells directed towards HLA-I; cellular stress), independent of the presented peptides. Our previous work on numerous HLA I molecules supports the idea that certain HLA I allo-types can be biochemically unstable, and that low protein stability can result in intracellular accumu-lation of misfolded HLA I proteins. In such cases, antigen presentation by HLA I is diminished at the cell surface, and accumulated HLA I can stimulate cellular stress pathways such as unfolded protein response (UPR). In this work, we will determine the stability of each individual HLA I protein associated with MHC-I-opathies, assess their link to cellular stress, and define common structural features among them. Finally, according to our expertise, we will perform screens with small molecules to improve their stability and prevent pathological phenotypes in cellular models.

主要组织相容性复合体（MHC） I类分子（被称为人类白细胞抗原（HLA I））对细胞内病原体和肿瘤的细胞毒性适应性反应至关重要。过继性反应的特异性依赖于来自每个个体的HLA- a、HLA- b和HLA- c基因座的两个等显性等位基因中，每六个可能不同的HLA- I分子中的一个准确而有效地呈现来自非自身（例如，病毒或肿瘤）蛋白的肽片段。自我与非自我的区别是通过消除自身反应性T细胞来保护的。然而，一组自身反应性疾病（如强直性脊柱炎和其他脊椎关节病、behet病、银屑病、鸟射性绒毛膜视网膜病）显示与单个HLA I等位基因有很强的遗传联系。在过去四十年中积累的大量遗传数据最近导致将这些自身反应性疾病分类为mhc - i病。有趣的是，在患病个体中，尚未检测到与疾病相关的CD8+ T细胞对特定肽- hla I复合物的反应。这表明存在额外的免疫机制（例如NK细胞对hla - 1的先天反应；细胞应激），独立于所呈现的肽。我们之前对大量HLA I分子的研究支持了这样一种观点，即某些HLA I同种异体可能是生化不稳定的，低蛋白稳定性可能导致错误折叠的HLA I蛋白在细胞内积聚。在这种情况下，HLA I在细胞表面的抗原呈递减少，积累的HLA I可以刺激细胞应激途径，如未折叠蛋白反应（UPR）。在这项工作中，我们将确定与mhc -I病变相关的每个HLA -I蛋白的稳定性，评估它们与细胞应激的联系，并确定它们之间的共同结构特征。最后，根据我们的专业知识，我们将对小分子进行筛选，以提高其稳定性并防止细胞模型中的病理表型。