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: 10416951
• 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/10416951
• 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; Calcium; Calcium Signaling; Cell Survival; Cells; Cellular Stress; Cellular Stress Response; Communication; Complex; Coupled; Development; Disease; Down-Regulation; Endoplasmic Reticulum; Exhibits; Failure; Genetic Screening; Genetic Transcription; Growth; Homeostasis; Human; Hypersensitivity; ITPR1 gene; Immune; Immune response; Immunity; Impairment; In Vitro; Inositol; Intention; Lead; Lymphocyte; Lymphoproliferative Disorders; Malignant - descriptor; Malignant lymphoid neoplasm; Measures; Mediating; Membrane; Mitochondria; Modeling; Mus; Mutation; Oxidative Stress; Pathway interactions; Pharmacology; Phosphatidylinositols; Phosphotransferases; Play; Predisposition; Production; 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; immune activation; immune function; improved; in vivo; insight; knock-down; new therapeutic target; novel; novel therapeutic intervention; overexpression; preservation; prevent; protein complex; receptor; 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 幼稚的淋巴细胞存在于静止状态，直到被抗原激活。他们继续 生存取决于他们通过抗原受体和稳态细胞因子收到的信号。 尚不清楚幼稚的淋巴细胞如何在继续保持静止的同时对临床信号反应。 这是一个重要的问题：增强对生存信号的反应可以推动恶性转变 静止受损会触发赞助免疫激活和免疫衰竭。我们最近有 发现了一种新的蛋白质复合物，其中含有磷脂蛋白酸性簇排序蛋白-1（PACS1）和WD 重复蛋白37（WDR37）是正常淋巴细胞存活和静止所必需的。小鼠缺乏 PACS1或WDR37缺乏循环的B和T细胞。 PACS1-WDR37缺乏B细胞暴露 体内的赞助增殖以及凋亡增加的增加，表明细胞的丧失 静止。这些细胞表现出体外内质网应激水平升高，并且 对氧化应激的高度敏感。重要的是，PACS1-WDR37缺乏症不会损害人类免疫力 回答。然而，它可能抑制凋亡障碍物引起的淋巴增生性疾病 途径。从机械上讲，pACS1或WDR37的缺失受损的抗原受体依赖性钙（Ca2+） 由于ER Ca2+释放的转录下调，从内质网（ER）释放 通道（肌醇三磷酸受体，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 生存和静止。我们将通过（i）阐明PACS1-WDR37的破坏来检验这一假设 减少B细胞存活和静止； （ii）定义PACS1-WDR37如何防止ER应力并促进 IP3R表达； （iii）验证PACS1-WDR37破坏是B细胞的治疗方法 恶性肿瘤。 与公共卫生有关： 允许淋巴细胞存活的信号网络在恶性转化过程中通常会选择。 有必要在保存时在淋巴细胞中颠覆促生存的信号传导 最有益的免疫功能。该建议将研究一个与 促进淋巴细胞的存活和静止，同时预防细胞应激，这是一种有希望的疗法 淋巴恶性肿瘤的靶标。