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

dc.contributor.author Huang, Kerui
dc.contributor.author Kim, Jinoh
dc.contributor.author Vo, Pham
dc.contributor.author Miao, Ting
dc.contributor.author Bai, Hua
dc.contributor.department Genetics, Development and Cell Biology
dc.date.accessioned 2022-03-28T13:41:56Z
dc.date.available 2022-03-28T13:41:56Z
dc.date.issued 2021-01-13
dc.description.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. Increasing evidence suggests that peroxisome import functions decline during aging. However, the transcriptome profiling of peroxisome import defects and how they affect disease development are still lacking. PEX5 encodes the cytoplasmic receptors for peroxisome-targeting signal types 1. We generate knock-in human HEK293 cells mutant using CRISPR to transiently express PEX5 cysteine 11 to alanine mutant (PEX5C11A), which blocks PEX5 recycling and exerts dominant negative effect on PEX5 mediated peroxisome import. To identify conserved responses, we perform transcriptomic analysis on Drosophila oenocyte-specific Pex1, Pex12 and Pex5 knockdowns and on human cells with impaired peroxisome import (PEX5C11A and PEX5 siRNA respectively). PEX5C11A induction triggers vast transcriptomic changes, including decreased oxidative phosphorylation, increased MAPK signaling and HIPPO signaling. PEX5 siRNA specifically decreases spliceosome activity and increases cholesterol metabolism. Using gene set enrichment analysis (GSEA), we identify protein processing in endoplasmic reticulum pathway, specifically ER-associated protein degradation (ERAD) pathway is induced in all PEX knockdowns in Drosophila. Peroxisome dysfunction elevates eIF2α phosphorylation in both Drosophila and human cell culture independent of XBP1 activation, suggesting increased integrative stress response (ISR). Moreover, peroxisome stress decreases ribosome biogenesis genes and impairs ribosome biogenesis in flies and human cells. Specifically, peroxisome stress impairs the 5’-ETS cleavage activity during the ribosome biogenesis and dampens 40S small ribosomal export in both flies and human. Our results suggest that reduced ribosome biogenesis and elevated ISR could be conserved cellular response to peroxisome import stress.
dc.description.comments This preprint is made available through bioRxiv at doi:https://doi.org/10.1101/2020.11.19.390609. It is made available under a CC-BY-ND 4.0 International license.
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/kv7k69yv
dc.language.iso en
dc.publisher © 2021 The Authors
dc.source.uri https://doi.org/10.1101/2020.11.19.390609
dc.title Peroxisome import stress impairs ribosome biogenesis and induces integrative stress response through eIF2α phosphorylation
dc.type Preprint
dspace.entity.type Publication
relation.isAuthorOfPublication ae16dcee-afdf-4805-9590-eb7a0bb1d0f1
relation.isOrgUnitOfPublication 7bab215d-4571-4c33-867c-28881af20485
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