The Role of Pacs1-Wdr37 inLymphocyte Quiescence and Survival

项目总结

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.