The Role of Pacs1-Wdr37 inLymphocyte Quiescence and Survival

Pacs1-Wdr37 在淋巴细胞静止和存活中的作用

• 批准号: 10569565
• 负责人: Evan Nair-Gill
• 金额: $ 41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-09 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569565
• 关键词: Acute; Affect; Antigen Receptors; Antigens; Apoptosis; Apoptotic; B lymphoid malignancy; B-Cell Antigen Receptor; B-Cell Leukemia; B-Cell Lymphomas; B-Lymphocytes; Behavior; Binding; Calcium; Calcium Signaling; Cell Survival; Cells; Cellular Stress; Communication; Complex; Coupled; Development; Disease; Down-Regulation; Endoplasmic Reticulum; Exhibits; Failure; Genetic Screening; Genetic Transcription; Growth; Homeostasis; Human; ITPR1 gene; Immune; Immune response; Immunity; Impairment; In Vitro; Inositol; Intention; Lymphocyte; Lymphocyte Activation; Lymphoproliferative Disorders; Malignant - descriptor; Malignant lymphoid neoplasm; Measures; Mediating; Membrane; Mitochondria; Modeling; Mus; Mutagens; Mutation; Oxidative Stress; Pathway interactions; Phosphatidylinositols; Phosphotransferases; Play; Predisposition; Production; Proliferating; Protein Biosynthesis; Protein Sortings; Proteins; Public Health; Reactive Oxygen Species; Receptor Signaling; Reporter; Role; Signal Transduction; Stress; T-Lymphocyte; Testing; Therapeutic; WD Repeat; Xenograft procedure; autoreactivity; biological adaptation to stress; cell transformation; cytokine; endoplasmic reticulum stress; genetic approach; humoral immunity deficiency; immune activation; immune function; improved; in vivo; insight; knock-down; new therapeutic target; novel; novel therapeutic intervention; overexpression; pharmacologic; preservation; prevent; protein complex; receptor; release of sequestered calcium ion into cytoplasm; response; therapeutic target; trafficking; tripolyphosphate

PROJECT SUMMARY Naïve lymphocytes exist in a quiescent state until becoming activated by antigen. Their continued survival depends on signals they receive through their antigen receptors and from homeostatic cytokines. How naïve lymphocytes respond to pro-survival signals while continually maintaining quiescence is unclear. This is an important issue: enhanced responses to survival signals can fuel malignant transformation while impaired quiescence can trigger spontaneous immune activation and immune failure. We have recently discovered a new protein complex containing phosphofurin acidic cluster sorting protein-1 (Pacs1) and WD repeat protein 37 (Wdr37) that is required for normal lymphocyte survival and quiescence. Mice lacking Pacs1 or Wdr37 were deficient in circulating B and T cells. Pacs1-Wdr37-deficient B cells exhibited spontaneous proliferation in vivo coupled with increased apoptosis which indicated loss of cellular quiescence. These cells demonstrated increased levels of endoplasmic reticulum stress in vitro and were hypersensitive to oxidative stress. Importantly, Pacs1-Wdr37 deficiency did not impair humoral immune responses. However, it potently suppressed lymphoproliferative diseases resulting from blocked apoptotic pathways. Mechanistically, deletion of Pacs1 or Wdr37 impaired antigen receptor-dependent calcium (Ca2+) release from the endoplasmic reticulum (ER) due to transcriptional downregulation of ER Ca2+ release channels (inositol triphosphate receptors, IP3R). These results lead us to hypothesize that Pacs1-Wdr37 integrates antigen receptor-dependent Ca2+ signaling and cellular stress responses to promote lymphocyte survival and quiescence. We will test this hypothesis by (i) elucidating how disruption of Pacs1-Wdr37 diminishes B cell survival and quiescence; (ii) defining how Pacs1-Wdr37 prevents ER stress and promotes IP3R expression; and (iii) validating Pacs1-Wdr37 disruption as a therapeutic approach to B cell malignancies. Relevance to public health: Signaling networks that permit lymphocyte survival are often co-opted during malignant transformation. There is a need for therapies that subvert pro-survival signaling in diseased lymphocytes while preserving most beneficial immune functions. This proposal will investigate a novel protein complex involved in promoting lymphocyte survival and quiescence while preventing cell stress that is a promising therapeutic target for lymphoid malignancies.

项目摘要 幼稚淋巴细胞以静止状态存在，直到被抗原激活。他们继续 存活取决于它们通过其抗原受体和从稳态细胞因子接收的信号。 幼稚淋巴细胞如何在持续保持静止的同时对促存活信号作出反应尚不清楚。 这是一个重要的问题：增强对生存信号的反应可能会助长恶性转化， 受损的静止可触发自发免疫激活和免疫失败。我们最近 发现了一种新的蛋白质复合物，含有磷酸弗林酸性簇分选蛋白1（Pacs 1）和WD 重复蛋白37（Wdr37），其是正常淋巴细胞存活和静止所需的。缺乏小鼠 Pacs 1或Wdr 37在循环B和T细胞中缺乏。Pacs1-Wdr37缺陷型B细胞表现出 体内自发增殖伴随凋亡增加，这表明细胞凋亡的丧失。 安静这些细胞在体外表现出增加的内质网应激水平， 对氧化应激过敏。重要的是，Pacs1-Wdr37缺陷不会损害体液免疫， 应答然而，它有效地抑制由细胞凋亡阻断引起的淋巴增生性疾病， 途径。从机制上讲，Pacs1或Wdr37的缺失损害了抗原受体依赖性钙（Ca2+） 由于ER Ca2+释放的转录下调而从内质网（ER）释放 三磷酸肌醇受体（inositol triphosphate receptor，IP3R）。这些结果使我们假设Pacs1-Wdr37 整合抗原受体依赖性Ca2+信号传导和细胞应激反应，以促进淋巴细胞 生存和平静。我们将通过（i）阐明Pacs1-Wdr37的破坏如何 减少B细胞存活和静止;（ii）定义Pacs1-Wdr37如何防止ER应激并促进 IP3 R表达;和（iii）验证Pacs1-Wdr37破坏作为B细胞的治疗方法 恶性肿瘤 与公共卫生的相关性： 在恶性转化过程中，允许淋巴细胞存活的信号网络经常被增选。 存在对破坏患病淋巴细胞中的促存活信号传导同时保留免疫应答的疗法的需求。 最有益的免疫功能。这项提议将研究一种新的蛋白质复合物， 促进淋巴细胞存活和静止，同时防止细胞应激，这是一种有前途的治疗方法， 淋巴恶性肿瘤靶点。