Grant Awarded in 2017

Investigating the mechanisms of cytotoxic granule exocytosis underlying hemophagocytic lymphohistiocytosis

Principal Investigator
Shuzo Sugita
University Health Network/U of Toronto
Toronto, ON Canada

Date of Award

December 2017

Amount of Award

Layperson Summary

Certain types of immune cells, such as natural killer (NK) cells and CD8+ T cells, fight diseases by releasing molecules that specifically target abnormal cells and invading pathogens in the body. This release process is dependent on a Ca2+ signal and occurs with the help of different proteins within the immune cells, which include Munc13-4 and syntaxin-11. Mutations in the gene coding for Munc13-4 protein result in terrible diseases such as Familial Hemophagocytic Lymphohistiocytosis 3 (FHL3) disease. Mutations in the gene coding for syntaxin-11 protein result in another type of FHL diseases called FHL4. Individuals with FHL3 or FHL4 suffer from diminished release from NK cells and CD8+ T cells. These patients present an uncontrolled number of active immune cells, which damage many vital organs. This strongly suggests the need to understand how Munc13-4 and syntaxin-11 help the release process in NK and CD8+ T cells, and how their defects impair the release resulting in immune disorders.

In this proposal, we will test new ideas that 1) Munc13-4 is a major Ca2+ sensor initiating the release process and that 2) Munc13-4 and syntaxin-11 bind and interact with each other, which regulates the release process. Our project seeks understand to how Ca2+ sensing segments on the Munc13-4 protein control the release. Importantly, we will study the mechanism in which Munc13-4 defects lead to FHL3, and how mutations in this protein influence the interaction with syntaxin-11 protein.

By studying the mechanism of the release process in NK cells, we can develop novel ideas to improve the release from immune cells of FHL patients. Therefore, current and future FHL patients will benefit from novel therapeutic procedures that can be developed from the information gained in this study.

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