Ca2+ signals:
Molecular Mechanisms and Integrative Functions Collaborative Research Center 894

Project A10 - Varsha Pattu & Jens Rettig

Molecular mechanisms of maturation, Ca2+-dependent fusion and endocytosis of lytic granules

Cytotoxic T lymphocytes (CTLs) are an essential part of the adaptive immune system as they prevent infections through the directed killing of infected cells. The killing occurs through the release of cytotoxic substances like perforin and granzymes from lytic granules (LGs) at the cell-cell contact area, the immunological synapse (IS). Despite the enormous importance of this process for e.g. human health the maturation of LGs, their protein composition and their fusion at the IS is not fully understood.

Based on our preliminary data we would like to answer the following questions in the proposed project:

1. What is the molecular composition of fusion-competent LGs?

2. Is the fusion process itself Ca2+-dependent and, if yes, which Ca2+ sensors are involved?

3. Is the “Ca2+-dependent activator protein for secretion (CAPS)” responsible for the priming of LGs or does it play other roles?

4. Does LG endocytosis exist and, if yes, which proteins are involved and what are the cellular intermediates before another round of exocytosis?

In addition, we would like to continue our efforts to identify the functions of specific domains in CAPS which might influence different processes like priming, Golgi maturation and vesicle filling in adrenal chromaffin cells.