Nava Segev - Regulation and coordination of intra-cellular trafficking pathways
Channel: Institut des Hautes Études Scientifiques (IHÉS)
Date: 2018-03-26

Our  research  is  aimed  at  understanding  how  a  basic  cellular  process,  trafficking  inside  cells,  is regulated.  
In the multiple intracellular trafficking pathways, proteins and membranes are transported between intracellular compartments.  Individual pathway steps are regulated by molecular switches 
termed Ypt/Rab GTPases, whose switching depends on upstream activators.  
Our  goal  is  to  elucidate  how  Ypt/Rab  GTPases  and  their  cognate  activators  regulate  individual transport  steps  and  coordinate  them  in  the  same  pathway  and  in  different  pathways.    Landmark discoveries about the mechanisms and machinery that underlie intracellular trafficking were made 
in  yeast  and  shown  to  pertain  to  humans.    Therefore,  we  are  using  yeast  as  a  model  system  to address  these  complicated  issues,  because  it  allows  easy  utilization  of  sophisticated  genetic approaches in combination with molecular and cellular methods.  Furthermore, the relatively small number of players (e.g., 11 Ypts in yeast versus ~70 Rabs in humans) and the resultant simplified interaction networks make yeast an excellent model for studying the coordination of transportsteps.  
Our  recent  findings  show  that  during  cell  growth,  Ypt1  and  Ypt31  GTPases  together  with  their activators  coordinate  transport  through  the  Golgi,  the  sorting  compartment  of  the  secretory pathway.  In contrast, under stress, Ypt1 with different activators regulate shuttling of cargo destined for recycling through the autophagy pathway.  
This  study  is  highly  relevant  to  human  health  because  multiple  essential  processes,  such  as secretion of hormones, presentation of receptors on the outer cell membrane, internalization of ligands  and  receptors,  and  response  to  stress,  depend  on  efficient  and  well-coordinated intracellular  trafficking.    Therefore,  impairment  of  trafficking  affects  every  system  in  the  human body, including the development and functioning of the brain, heart, and immune system.  Human 
homologs of the yeast trafficking regulators we study were implicated in multiple human illnesses, including cancer and neurodegenerative diseases.