Retrograde signaling pathways between different cellular organelles (such as mitochondria or ER) and the nucleus have been identified over the years. These retrograde signaling pathways have been shown to activate the expression of organelle-specific quality control proteins, in order to maintain the organelles' function in response to organelle-specific stress. Until now, the existence of a retrograde signaling pathway for other organelles such as peroxisomes had remained elusive. Using the nematode Caenorhabditis elegans, we identified for the first time such signaling for peroxisomes. Specifically, we showed that peroxisomal import stress caused by the knock-down of
prx-5, the homolog of the human peroxisomal matrix import receptor PEX5, triggers a peroxisomal retrograde signaling (PRS). We show that the PRS is dependent on the transcription factor NHR-49, the homolog of human PPARalpha and its co-factor MDT-15, the homolog of human Mediator MED15. Lipidomic analysis revealed that
prx-5 knock-down causes increased levels of triacylglycerols with longer acyl chains, which are normally broken-down by peroxisomal beta-oxidation. The presence of excess long chain fatty acids could represent the signal that activates the PRS. Consistent with this hypothesis, we found that directly perturbing peroxisomal beta-oxidation is sufficient to activate the PRS. Using transcriptomic/proteomic approaches we found that peroxisomal import stress also induces the up-regulation of peroxisomal lipid metabolism, which could represent a mechanism to cope with the reduced beta-oxidation. Additionally, proteins involved in the immune response are up-regulated, and we found that the PRS is activated upon infection with Pseudomonas aeruginosa. The PRS thus may fulfill two functions, maintaining the homeostasis of lipid metabolism and acts as a potential surveillance mechanism to protect against pathogens