The Role of Pacs1-Wdr37 inLymphocyte Quiescence and Survival

项目总结 幼稚的淋巴细胞处于静止状态，直到被抗原激活。他们的续集 生存依赖于它们通过抗原受体和稳态细胞因子接收到的信号。 幼稚的淋巴细胞如何在持续保持静止的情况下对支持生存的信号做出反应尚不清楚。 这是一个重要的问题：对生存信号的增强反应可以促进恶性转化，而 静止期受损会引发自发的免疫激活和免疫衰竭。我们最近做了 发现一种新的含有磷酸呋喃酸性簇分类蛋白-1(Pacs1)和WD的蛋白质复合体 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 循环B、T细胞中Pacs1或Wdr37缺失。Pacs1-Wdr37缺陷的B细胞 体内自发增殖与细胞凋亡增加相结合，表明细胞丢失 宁静。这些细胞在体外表现出内质网应激水平的增加，并 对氧化应激高度敏感。重要的是，Pacs1-Wdr37缺陷不会损害体液免疫 回应。然而，它有效地抑制了因细胞凋亡受阻而导致的淋巴增生性疾病。 小路。从机制上讲，Pacs1或Wdr37的缺失会损害抗原受体依赖性钙离子(Ca2+) 内质网(ER)钙释放的转录下调 通道(三磷酸肌醇受体，IP3R)。这些结果使我们假设Pacs1-Wdr37 整合抗原受体依赖的钙信号和细胞应激反应促进淋巴细胞 生存和平静。我们将通过(I)阐明Pacs1-Wdr37的中断如何检验这一假设 减少B细胞的存活和静止；(Ii)确定Pacs1-Wdr37如何预防内质网应激并促进 IP3R表达；以及(Iii)验证Pacs1-Wdr37中断作为B细胞治疗方法的有效性 恶性肿瘤。 与公共卫生的相关性： 允许淋巴细胞存活的信号网络通常在恶性转化过程中被增选。 需要一种治疗方法来颠覆疾病淋巴细胞中支持生存的信号，同时保存 最有益的免疫功能。这项提案将研究一种新的蛋白质复合体，它涉及 促进淋巴细胞存活和静止，同时防止细胞应激，这是一种有希望的治疗方法 淋巴系统恶性肿瘤的靶点。

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.