Depletion of LONP2 unmasks differential requirements for peroxisomal function between cell types and in cholesterol metabolism

Peroxisomes play a central role in tuning metabolic and signaling programs in a tissue- and cell-type-specific manner. However, the mechanisms by which the status of peroxisomes is communicated and integrated into cellular signaling pathways are not yet understood. Herein, we report the cellular responses to peroxisomal proteotoxic stress upon silencing the peroxisomal protease/chaperone LONP2. Depletion of LONP2 triggered the accumulation of its substrate TYSND1 protease, while the overall expression of peroxisomal proteins, as well as TYSND1-dependent ACOX1 processing appeared normal, reflecting early stages of peroxisomal proteotoxic stress. Consequently, the alteration of peroxisome size and numbers, and luminal protein import failure was coupled with induction of cell-specific cellular stress responses. Specific to COS-7 cells was a strong activation of the integrated stress response (ISR) and upregulation of ribosomal biogenesis gene expression levels. Common changes between COS-7 and U2OS cell lines included repression of the retinoic acid signaling pathway and upregulation of sphingolipids. Cholesterol accumulated in the endomembrane compartments in both cell lines, consistent with evidence that peroxisomes are required for cholesterol flux out of late endosomes. These unexpected consequences of peroxisomal stress provide an important insight into our understanding of the tissue-specific responses seen in peroxisomal disorders.

Automated summary

Peroxisomes play a central role in regulating metabolic and signaling pathways, but the mechanisms by which peroxisome status is communicated and integrated into cellular signaling pathways are not well understood. In this study, the cellular responses to peroxisomal proteotoxic stress were investigated. It was found that depletion of the peroxisomal protease/chaperone LONP2 led to cell-specific stress responses, including the activation of the integrated stress response (ISR) and upregulation of ribosomal biogenesis gene expression levels in COS-7 cells. Common changes between COS-7 and U2OS cell lines included repression of the retinoic acid signaling pathway and upregulation of sphingolipids. Accumulation of cholesterol in endomembrane compartments was observed in both cell lines. These unexpected consequences of peroxisomal stress provide important insights into tissue-specific responses in peroxisomal disorders.