Research Summary

Role of small GTP-binding proteins in regulating lysosomal trafficking and microbial killing

With the advent of compartmentalization in eukaryotic organisms, it became crucial for proteins to traffic to their correct location within the cell and therefore need for constant communication between these compartments. Membrane trafficking is a fundamental process that mediates the directed movement of proteins and membranes between different cellular locations, critical for the proper functioning of all eukaryotic cells. The primary research interests of my laboratory focus on studying the molecular mechanisms regulating the trafficking towards late endosomes and lysosomes. Lysosomes are membrane-bound organelles present in eukaryotes whose catabolic function is essential for maintaining general cellular homeostasis. In my laboratory, we are studying the function of small GTPases and tethering factor complexes that are present on lysosomes and regulate endocytic, phagocytic and autophagic traffic towards lysosomes (see schematic in Figure 1). The importance of these proteins is reflected by the fact that pathogens such as Mycobacterium.tuberculosis or Salmonella evade killing in the host lysosome by targeting these protein complexes. On the other hand, recent studies have shown that Ebola and Marburg filoviruses that cause rapidly fatal haemorrhagic fever in humans use lysosomal tethering complexes to escape from endosomes and establish infection. Our findings will contribute to a better understanding of the mechanism by which the endocytic regulatory proteins including small GTPases and tethering factors regulates lysosomal trafficking, proper functioning of which is critical for cellular survival and defense against pathogens. Additionally, the proposed studies have practical applications for the development of new therapeutic approaches to induce the clearance of intracellular bacteria and viruses by our cells.

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Figure Legend: Schematic of traffic route towards lysosomes: Lysosomes are membrane-bound organelles present in eukaryotes who receive extracellular cargo from endocytic and phagocytic route and intracellular cargo via autophagic pathways. Small GTP-binding proteins of the Rab, Arf and Arf-like (Arl) family localize to distinct intracellular membranes and recruit their effectors including tethering factors to meditate cargo trafficking and vesicular fusion. The primary research interests of my lab focus on how trafficking towards lysosomes is regulated by action of small GTPases of Rab and Arf family and their effectors including tethering factors such as the HOPS complex. Homotypic fusion and Protein Sorting (HOPS) complex is an evolutionarily conserved multi-subunit tethering factor complex that regulates endo-lysosomal fusion.