Nicholas Ktistakis

Research

PA and its effectors

In collaboration with Dr Raghu Padinjat we have shown that manipulation of specific PA species in Drosophila photoreceptors affects the structure and function of the endomembrane system. This is in keeping with one role of PA, as a regulator of trafficking pathways. In other experiments we have identified the PA binding site on two PA effectors, SK1 and phosphatidylinositol 4-phosphate 5-kinase. In both of these cases, the PA-protein interaction appears to be important for membrane localization and enzymatic activity. We are focusing most of our current PA work on the biological consequences of the PA-SK1 interaction.

PI3P and nutrient sensing

PI3 paradox

Under plentiful nutrients, PI3P appears to regulate in part the activity of the protein kinase target of rapamycin (TOR), a master regulator of cell growth. Upon nutrient depletion, TOR becomes inactivated and another pool of PI3P regulates the induction of autophagy, a conserved cellular response for the generation of nutrients from self digestion (Figure 1 – left).

We have recently shown that PI3P regulates autophagy by accumulating on novel membrane termed omegasomes which are connected to the ER and help form some autophagosomes (Figure 4 – below right).

Autophagosomes are the double membrane vesicles that deliver material to the lysosomes during autophagy, and several proteins involved in autophagosome formation are known to be PI3P effectors.

Currently, we are trying to identify the genetic and biochemical requirements of omegasome formation, and we are also exploring several hypotheses on the mechanism of TOR activation by PI3P.
Autophagosomes