Peroxisome import stress impairs ribosome biogenesis and induces integrative stress response through eIF2α phosphorylation

Abstract

Peroxisome biogenesis diseases (PBDs) are characterized by global defects in peroxisomal function and can result in severe brain, liver, kidney, and bone malfunctions. PBDs are due to mutations in peroxisome biogenesis factors (PEX genes) that are responsible for peroxisome assembly and function. There is increasing evidence suggesting that peroxisome import functions decline during aging. The transcriptome profiling of peroxisome import defects is still lacking. To identify conserved responses, we undertook a bioinformatic transcriptomic analysis on Drosophila oenocyte specific Pex1, Pex12 and Pex5 knockdowns. In addition, we performed analysis on human cells with induced peroxisome import stress. We uncovered that oenocyte-specific Pex1, Pex12 and Pex5 have distinct transcriptional profiles with each other. Using gene set enrichment analysis (GSEA), we identified protein processing in endoplasmic reticulum pathway, specifically ER-associated protein degradation (ERAD) pathway is enriched and induced in all PEX knockdowns in Drosophila. Moreover, we uncovered decreased expression in ribosome biogenesis genes in flies and human cells. Indeed, we identified a stall at the 5’-ETS cleavage sites during the ribosome biogenesis and impaired 40S small ribosomal export in both flies and human. Our data indicates an unexpected link between peroxisome and ribosome biogenesis. Our results suggest that reduced ribosome biogenesis could be conserved cellular response to reduce peroxisome import stress.

Peroxisomal Stress Response and Inter-Organelle Communication in Cellular Homeostasis and Aging

“…Accordingly, the silencing of PEX2 in human liver hepatocarcinoma cell lines induced the mRNA expression of ER stress markers such as PERK, Erol-Lα, PDI, and CHOP [ 122 ]. Our recent study also supports the link between peroxisomal dysfunction and ER stress [ 9 ]. We found that the ER-associated protein degradation (ERAD) pathway was induced in Pex1 , Pex5 , and Pex12 knockdowns in Drosophila.…”

“…Several lines of evidence suggest that an uncharacterized cellular stress response pathway might exist in eukaryotic cells to cope with peroxisomal dysfunction. Recent studies have revealed global transcriptional changes in PEX mutants with impaired peroxisomal import [ 9 , 68 , 69 , 70 , 71 , 72 ]. Peeters et al [ 68 ] investigated the role of peroxisomes in liver carbohydrate metabolism through a microarray analysis using hepatocyte-specific Pex5 knockout mice ( L-Pex5 −/− mice).…”

“…Recently, we performed a comparative transcriptomic analysis to interrogate the conserved peroxisomal stress responses between the fruit fly and humans. We generated stable human HEK293 cells with doxycycline-inducible expression of a mutated PEX5 (PEX5 C11A ), which blocks PEX5 recycling and PEX5-mediated peroxisomal import [ 9 ]. PEX5 C11A expression decreased the mRNA level of genes involved in mitochondrial oxidative phosphorylation and increased the mRNA level of genes involved in MAPK signaling and Hippo signaling, presumably due to increased ROS production.…”

“…Our transcriptome analysis showed that oxidative phosphorylation genes were repressed, and the inflammation pathway was induced upon peroxisomal stress in both fly and human cells. Furthermore, we found that peroxisomal dysfunction in both fly and human cells repressed ribosome biogenesis and activated ER stress response pathways, especially the eIF2α-ATF4 pathway, suggesting potential crosstalk between peroxisomes and the ER [ 9 ].…”

“…More recently, it has become clear that peroxisome deficiency can also alter functions of specific subcellular organelles [ 5 , 6 , 7 ], such as mitochondria, endoplasmic reticulum (ER), and lysosome. Peroxisomal stress signals can also be transduced from peroxisomes to the nucleus, as peroxisomal dysfunction often induces global transcriptional changes [ 8 , 9 ]. Thus, similar to other organelle stress pathways (e.g., ER stress), there are specific peroxisomal stress response pathways that allow eukaryotic cells to cope with malfunctioning peroxisomes [ 10 ].…”