The role for ER associated degradation (ERAD) in T cell homeostasis and memory

ER 相关降解 (ERAD) 在 T 细胞稳态和记忆中的作用

• 批准号: 10582915
• 负责人: Shannon A. Carty
• 金额: $ 58.46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-17 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582915
• 关键词: Acute; Antigens; Apoptotic; Area; Biochemical Pathway; CD8-Positive T-Lymphocytes; Cell Death; Cell Survival; Cells; Cessation of life; Chronic; Communicable Diseases; Complex; Cytosol; Data; Endoplasmic Reticulum; Epigenetic Process; Equilibrium; Genetic; Genetic Transcription; Goals; Homeostasis; Human; Immune; Immune response; Immunity; In Vitro; Infection; Knockout Mice; Knowledge; Lymphocytic choriomeningitis virus; Maintenance; Malignant Neoplasms; Measurement; Mediating; Mediator; Memory; Metabolic dysfunction; Metabolism; Molecular; Mus; Pathway interactions; Proteins; Public Health; Quality Control; Reporter; Research; Rest; Role; Signal Pathway; Signal Transduction; T cell differentiation; T cell response; T-Lymphocyte; Testing; Therapeutic; Transgenic Organisms; Ubiquitin; Vaccination; Virus Diseases; Work; arm; design; endoplasmic reticulum stress; experience; improved; in vivo; inhibitor; insight; misfolded protein; mitochondrial metabolism; new therapeutic target; novel; pathogen; pharmacologic; preservation; prevent; proteostasis; response; tumor; vaccine response

PROJECT SUMMARY CD8+ T cells are critical to eradicate viral infections and tumors, as well as providing long-lasting protection; however, not all immune responses elicit functional and durable immune responses leading to loss of protection against intracellular pathogens and cancer. Effective T cell immunity requires tight control to maintain the appropriate equilibrium between cellular quiescence, activation and cell death. Elegant work has been done to elucidate the transcriptional, epigenetic and metabolic networks that regulate T cells. In contrast, much less is known about how cellular protein homeostasis (proteostasis) regulates CD8+ T cell fate. Proteostasis is maintained primarily through the endoplasmic reticulum associated degradation (ERAD) and unfolded protein response (UPR) pathways. ERAD complexes recognize misfolded proteins in ER and translocate them into the cytosol for proteasomal degradation. Sel1L is a critical component of the ERAD complex, facilitating the recognition, retro-translocation and subsequent proteasomal degradation of misfolded proteins in the ER. Though the role of the UPR has been studied in T cell responses, nothing is known how Sel1L/ERAD controls CD8+ T cell fate. Using conditional deletion of Se1lL in murine T cells to disrupt ERAD, we recently identified a novel role for ERAD in T cell quiescence and survival at steady-state. In additional preliminary results, we demonstrate that antigen-specific CD8+ T cells experience dynamic ER stress during acute viral infection and Sel1L is required to protect antigen-specific CD8+ T cells in a cell-intrinsic manner from cell death following viral infection. Our long-term goal is to identify molecular mechanisms that regulate T cell fates and discover novel therapeutic targets that can be used to modulate human T cell responses against infections and tumors. The objective of this proposal is to dissect how Sel1L/ERAD regulates CD8+ T cell fate at steady-state and following infection. Our central hypothesis is that Sel1L/ERAD is required to maintain cellular proteostasis in CD8+ T cells during homeostasis and following antigen activation. To test our central hypothesis, we will pursue the following aims: 1) to determine how Sel1L/ERAD regulates CD8+ T cell homeostasis and 2) to dissect the mechanisms by which Sel1L/ERAD preserves CD8+ T cells following antigen activation. In this proposal, we will identify how Sel1L/ERAD protects naïve and activated CD8+ T cells against dysregulated proteostasis, inappropriate UPR activation and altered cellular metabolism. The completion of these aims will lead to knowledge that has the potential for offering new therapeutic targets that can enhance T cell responses to viral infections and improve protective vaccines responses.

项目概要 CD8+ T 细胞对于根除病毒感染和肿瘤至关重要，并提供 持久的保护；然而，并非所有的免疫反应都会引发功能性和持久的免疫 导致失去对细胞内病原体和癌症的保护的反应。 细胞免疫需要严格控制以维持细胞之间的适当平衡 已经完成了优雅的工作来阐明静止、激活和细胞死亡。 相比之下，调节 T 细胞的转录、表观遗传和代谢网络则少得多。 了解细胞蛋白稳态（蛋白质稳态）如何调节 CD8+ T 细胞的命运。 蛋白质稳态主要通过内质网相关的降解来维持 (ERAD) 和未折叠蛋白反应 (UPR) 复合物识别错误折叠。 Sel1L 是一种蛋白质，可将内质网中的蛋白质转运至细胞质中进行蛋白酶体降解。 ERAD 复合物的关键组成部分，促进识别、逆转录易位和 随后，蛋白酶体降解了内质网中错误折叠的蛋白质。 UPR 已在 T 细胞反应中进行了研究，但尚不清楚 Sel1L/ERAD 如何控制 CD8+ T 我们最近利用小鼠 T 细胞中 Se1lL 的条件性缺失来破坏 ERAD。 此外，还发现了 ERAD 在 T 细胞静止和稳态存活中的新作用。 初步结果表明，抗原特异性 CD8+ T 细胞经历动态 ER 急性病毒感染期间的应激和 Sel1L 是保护抗原特异性 CD8+ T 细胞所必需的 我们的长期目标是确定病毒感染后细胞死亡的细胞固有方式。 调节 T 细胞命运的分子机制并发现新的治疗靶点 用于调节人类 T 细胞针对感染和肿瘤的反应。 该提案旨在剖析 Sel1L/ERAD 如何在稳态和稳态下调节 CD8+ T 细胞的命运 我们的中心假设是 Sel1L/ERAD 是维持细胞状态所必需的。 CD8+ T 细胞在稳态期间和抗原激活后的蛋白质稳态。 中心假设，我们将追求以下目标：1）确定Sel1L/ERAD如何 调节 CD8+ T 细胞稳态，2) 剖析 Sel1L/ERAD 的机制 在本提案中，我们将确定如何在抗原激活后保留 CD8+ T 细胞。 Sel1L/ERAD 保护幼稚和活化的 CD8+ T 细胞免受蛋白质稳态失调的影响， 不适当的 UPR 激活和细胞代谢的改变将实现这些目标。 产生有可能提供新的治疗靶点的知识，这些靶点可以增强 细胞对病毒感染的反应并改善保护性疫苗反应。