TOR and heat shock response pathways regulate peroxisome biogenesis during proteotoxic stress

Nandini Shukla (), Maxwell L. Neal, Jean-Claude Farré, Fred D. Mast, Rajasri Sarkar, Linh Truong, Theresa Simon, Leslie R. Miller, John D. Aitchison and Suresh Subramani ()
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Nandini Shukla: University of California, San Diego, Department of Molecular Biology, School of Biological Sciences
Maxwell L. Neal: Seattle Children’s Research Institute, Center for Global Infectious Disease Research
Jean-Claude Farré: University of California, San Diego, Department of Molecular Biology, School of Biological Sciences
Fred D. Mast: Seattle Children’s Research Institute, Center for Global Infectious Disease Research
Rajasri Sarkar: University of California, San Diego, Department of Molecular Biology, School of Biological Sciences
Linh Truong: University of California, San Diego, Department of Molecular Biology, School of Biological Sciences
Theresa Simon: University of California, San Diego, Department of Molecular Biology, School of Biological Sciences
Leslie R. Miller: Seattle Children’s Research Institute, Center for Global Infectious Disease Research
John D. Aitchison: Seattle Children’s Research Institute, Center for Global Infectious Disease Research
Suresh Subramani: University of California, San Diego, Department of Molecular Biology, School of Biological Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Peroxisomes are versatile organelles mediating energy homeostasis and redox balance. While peroxisome dysfunction is linked to numerous diseases, the mechanisms regulating peroxisome dynamics during cellular stress remain elusive. Using yeast, we show that proteotoxic stress, including loss of endoplasmic reticulum (ER) or cytosolic chaperone function, impaired ER protein translocation, disrupted N-linked glycosylation, or reductive stress, triggers peroxisome proliferation. This occurs through increased de novo biogenesis from the ER, as well as growth and division, rather than impaired pexophagy. Peroxisome biogenesis is essential for cellular recovery from proteotoxic stress. Through comprehensive testing of major signaling pathways, we determine this response to be mediated by activation of the heat shock response and inhibition of Target of Rapamycin (TOR) signaling. Notably, the effects of proteotoxic stress and TOR inhibition on peroxisomes are also observed in human fibroblasts. Our findings reveal a critical and conserved role of peroxisomes in cellular response to proteotoxic stress.

Date: 2025
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DOI: 10.1038/s41467-025-65776-y

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