Peroxisomal retrograde signaling in C. elegans

• Applicant: Dr. Stephane Rolland
• Subject Area: Cell Biology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323205681

Ensuring that proteins acquire and maintain their proper conformation is essential as unfolded proteins not only are inactive but also tend to form toxic aggregates. The quality control of proteins is mediated by chaperones which help proteins to acquire their proper conformation as well as proteases which degrade unfolded proteins thereby preventing them from forming aggregates. While protein quality control occurs at all time, it can be transcriptionally up-regulated in response to increased stress. This stress response also called unfolded protein response (UPR) has been shown to exist in several compartments of the cell, allowing the cell to respond to unfolded protein stress locally. While UPRs have been identified in the cytosol, the ER and the mitochondria, the existence of such a response in other compartments such as peroxisomes remains elusive. Peroxisomes participate in several key biological processes (such as breakdown of fatty acids for energy production and degradation of toxic molecules such as hydrogen peroxide). These organelles are essential as defects in their biogenesis have been associated with a group of fatal diseases, the Zellweger Syndrome Disorders. Understanding how quality control of peroxisomal proteins is achieved is therefore not only a very important basic biological question but it may also help to get a better understanding of these diseases. While there is evidence that the peroxisomal Lon protease participates in the quality control of peroxisomal matrix proteins, whether this protease is regulated in response to stress remains unclear. I have recently shown that affecting peroxisomal biogenesis in the nematode Caenorhabditis elegans leads to the up-regulation of the expression of the peroxisomal Lon protease, revealing for the first time the existence of a retrograde signaling from the peroxisome to the nucleus. My future research is aimed at understanding how peroxisomes communicate with the nucleus in the context of peroxisomal protein quality control. Specifically, I propose to first identify the signal(s) triggering this retrograde signaling pathway (Objective 1). With a combination of proteomic and genetic approaches I propose to determine the molecular basis of this retrograde signaling pathway (Objective 2).

• DFG Programme: Research Grants