Molecular mechanisms of exocytosis coordination

Cytotoxic lymphocytes (called cytotoxic T cells (Tc) and natural killer (NK) cells are an essential component of our immune system. These highly specialized immune cells can recognize and kill tumor or virus-infected cells via targeted release of cytolytic vesicles containing molecules that induce cell death. This process is tightly regulated to ensure its efficacy and, at the same time, avoid collateral damage to healthy cells. Complete or partial ablation of CTL and NK cell cytotoxicity causes life-threatening disease or may predispose to cancer. In a recent study (Kalinichenko et al., Blood, 2021), scientists at the St. Anna Childrens Cancer Research Institute (CCRI) identified a new etiology of a life-threatening disease called familial hemophagocytic lymphohistiocytosis (HLH). In their work, scientists have shown that the disease is caused by inherited mutations in the gene encoding protein RhoG, which is essential for the cytotoxic function of Tc and NK cells. The researchers discovered that RhoG controls several intercellular pathways to coordinate the polarized release of cytolytic molecules for the efficient killing of target cells. This unique role of RhoG in the coordination of cytotoxic function has never been reported before and requires further investigation on a molecular level. Researchers from the CCRI have shown that RhoG can physically interact with cytoskeleton regulators and components of exocytosis machinery. Coordination of these two pathways required for precise and polarized release of cytolytic molecules towards target cells. The first step vesicle delivery - requires the activity of the cellular cytoskeleton. While the second step is mediated by the specialized exocytosis proteins that anchor cytolytic vesicles to the membrane and fuse them. In the current project, scientists aim to investigate RhoG- mediated coordination of cytoskeleton and exocytosis proteins in space and time. This study will provide a deeper understanding of the exocytosis regulation on a molecular level and provide a basis for exploring new therapeutic approaches.