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Open AccessArticle

Ochratoxin A Sequentially Activates Autophagy and the Ubiquitin-Proteasome System

1
Molecular Toxicology and Cancer Research Laboratory, Department of Molecular Biology and Genetics, Bogazici University, Bebek-Istanbul 34342, Turkey
2
Center for Life Sciences and Technologies, Bogazici University, Bebek-Istanbul 34342, Turkey
*
Author to whom correspondence should be addressed.
Toxins 2019, 11(11), 615; https://doi.org/10.3390/toxins11110615
Received: 18 September 2019 / Revised: 12 October 2019 / Accepted: 23 October 2019 / Published: 24 October 2019
(This article belongs to the Section Mycotoxins)
Ochratoxin A (OTA) is a carcinogenic mycotoxin, which is produced by Aspergillus and Penicillium genera of fungi and commonly contaminates food and feed. We and others have previously shown that OTA causes sustained activation of PI3K/AKT and MAPK/ERK1-2 signaling pathways in different cell types and animal models. Given the close relationship between cellular signaling activity and protein stability, we were curious whether increased PI3K/AKT and MAPK/ERK1-2 signaling may be the result of OTA-stimulated alterations in proteolytic activity. We show that both of the major proteolytic systems, autophagy, and the ubiquitin-proteasome system (UPS), are activated upon OTA exposure in human kidney proximal tubule HK-2 and mouse embryonic fibroblast (MEF) cells. OTA stimulates transient autophagic activity at early time points of treatment but autophagic activity subsides after 6 h even in the sustained presence of OTA. Interestingly, OTA exposure also results in increased cell death in wild-type MEF cells but not in autophagy-halted Atg5-deficient cells, suggesting that autophagy exerts a pro-death effect on OTA-induced cytotoxicity. In addition, prolonged OTA exposure decreased ubiquitinated protein levels by increasing proteasomal activity. Using purified and cellular proteasomes, we observed enhanced chymotrypsin-, caspase-, and trypsin-like activities of the 26S but not the 20S proteasome in the presence of OTA. However, in the cellular context, increased proteasomal activity depended on prior induction of autophagy. Our results suggest that autophagy and subsequent UPS activation are responsible for sustained activation of PI3K/AKT and MAPK/ERK1-2 pathways through regulating the levels of critical phosphatases VHR/DUSP3, DUSP4, and PHLPP, which are known to be involved in OTA toxicity and carcinogenicity. View Full-Text
Keywords: ochratoxin A; ubiquitin-proteasome system; autophagy; proteolytic pathways; PI3K/AKT; MAPK/ERK1-2 ochratoxin A; ubiquitin-proteasome system; autophagy; proteolytic pathways; PI3K/AKT; MAPK/ERK1-2
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Akpinar, H.A.; Kahraman, H.; Yaman, I. Ochratoxin A Sequentially Activates Autophagy and the Ubiquitin-Proteasome System. Toxins 2019, 11, 615.

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