La palmitoylation : régulateur clé du triage et du trafic intracellulaire

 

Stéphane Lefrançois

Hôpital Maisonneuve-Rosemont

 

Domaine : neurosciences, santé mentale et toxicomanies

Programme chercheurs-boursiers - Junior 2

Concours 2014-2015

The efficient sorting and trafficking of proteins in the cell has important consequences in human health. Proteins must be localized to specific intracellular compartments to function effectively. As such, mutations in genes that control the intracellular distribution of proteins have been linked to rare diseases such as Tay Sachs, Gaucher's and Charcot-Marie-Tooth syndrome but also to more prevalent diseases such as cancer, diabetes and Alzheimer's.

Our goal is to identify and characterize the mechanism cells use to control the intracellular distribution of proteins to increase our understanding of fundamental cell biology and to use this knowledge to identify novel therapeutic targets. The function, turnover and localization of proteins can be modulated by a number of modifications such as the addition of sugars and lipids. We and others have shown that palmitoylation, a fatty modification found on proteins, is important in the efficient localization of a number of proteins. However, the mechanism the cell uses to add and remove this modification has not been fully investigated. We have shown that palmitoylation is important in the localization and for the stability of the lysosomal sorting receptor.

Additionally, we have identified and characterized the machinery that modifies these lysosomal sorting receptors. Functionally, if the machinery is absent or the receptor can not be modified due to a mutation in the sorting receptor itself, then the receptor is degraded. This leads to the improper sorting of lysosomal cargo and eventually cell death. A number of proteins implicated in the diseases mentioned above are modified by palmitoylation. Our work will lead to a greater understanding of the molecular details the cell employs to sort and traffic proteins which could lead to an increase in our knowledge of the mechanism of variety of diseases and offer novel therapeutic strategies.