Rackles, Elisabeth et al. (2021) International Worm Meeting "Impaired peroxisomal import triggers a peroxisomal retrograde signaling"

Ewbank, Jonathan, Forne , Ignasi, Imhof, Axel, Rolland, Stephane, Fischer, Christian, Zhang, Xing, Zacherl, Judith, Osman, Christof, Rackles, Elisabeth, Witting, Michael, Schrott, Simon

[International Worm Meeting, 2021]

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

Amanda Kahn-Kirby et al. (2006) Neuronal Development, Synaptic Function, and Behavior Meeting "Genetic Analysis of a C. elegans Neuronal Fat Regulatory Pathway"

Amanda Kahn-Kirby, Kaveh Ashrafi

[Neuronal Development, Synaptic Function, and Behavior Meeting, 2006]

Studies of rare familial human obesity syndromes have revealed a handful of genes that act in the mammalian brain to coordinate fat storage. Two of these genes, the basic helix-loop-helix (bHLH) transcription factors Sim1 and NHLH2, function in the development of key brain regions for feeding regulation. Mice lacking Sim1 or NHLH2 are obese, and have defects in development of the hypothalamus(1, 2). In addition, Sim1 disruption is associated with rare occurrences of profound human obesity(3, 4). Little is known about the signaling pathways and neural circuits used by Sim1 and NHLH2 to promote energy balance. C. elegans has homologues of Sim1 (T01D3.2) and NHLH2 (hlh-15/C43H8.6). Remarkably, RNAi inactivation of each of these genes results in increased fat content; animals with mutations in hlh-15 also have increased fat content. Furthermore, RNAi knockdown of the NHLH2 homologue hlh-15 diminishes feeding (Elisabeth Greer and Kaveh Ashrafi, personal communication). Interestingly, postembryonic expression of each of these genes is limited to just three non-overlapping neurons each, including interneurons without previously-described roles in energy balance regulation. Stage-specific RNAi knockdown experiments are in progress to distinguish developmental and post-developmental functions of these two transcription factors. Studies are underway to identify genetic networks that are misregulated in animals lacking T01D3.2 or hlh-15. These include transcriptional approaches and analysis of candidate genes. We anticipate that our studies will reveal upstream regulators of these genes, as well as their downstream transcriptional and metabolic targets. Given the remarkable conservation of both neuronal expression and fat regulatory function across metazoa, we speculate that our analysis of C. elegans bHLH-dependent pathways will reveal core components of conserved energy balance networks.