Induction of proteotoxic stress by the mycotoxin patulin

Abstract

Patulin is a naturally occurring mycotoxin produced by a number of molds and may contaminate a wide variety of food products. In practice, patulin’s main societal relevance concerns apple juice and its products. Multiple advisory bodies, including the U.S. Food and Drug Administration and the World Health Organization, recommend that producers monitor and limit patulin levels in apple juice products. The mechanism of patulin toxicity remains largely unknown. Here we show that patulin induces proteotoxic stress in the yeast S. cerevisiae. The transcription factor Rpn4 controls the abundance of the proteasome, the complex multisubunit protease that destroys proteins, including misfolded proteins. Rpn4 protein is strongly induced by patulin, and Rpn4 levels normalize over time, consistent with homeostatic regulation. A rpn4Δ mutant is highly sensitive to patulin, confirming the physiologic relevance of this response. Rpn4 is known to be regulated both transcriptionally and post-translationally. Patulin induces both pathways of regulation, but the post-transcriptional pathway predominates in controlling Rpn4 protein levels. These results indicate that proteotoxicity represents a major aspect of patulin toxicity. They not only have implications for patulin detoxification but in addition suggest the possibility of some potentially useful patulin applications.

Targeted Degradation of Glucose Transporters Protects against Arsenic Toxicity

“…This experiment was carried out in the pdr5Δ mutant background to increase the intracellular levels of bortezomib. Note that arsenic alone induces strong proteotoxic effects, as indicated by the increase in both high-molecular-weight ubiquitinated material and Tmc1 (compare the first and second lanes), consistent with prior reports (24,49). Numbers on the left are molecular masses (in kilodaltons).…”

Distinct Transcriptional Changes in Response to Patulin Underlie Toxin Biosorption Differences in Saccharomyces cerevisiae

“…The effect of PAT in eukaryotic cells has been largely studied [25]. PAT is a strong electrophile which is able to interact with different types of macromolecules, among which PAT is highly reactive with free thiol groups, such as those contained in cysteine residues [44]. Interestingly, in response to PAT, the WE isolate induced the expression of several genes involved in different steps of glutathione, methionine and cysteine biosynthesis, such as those conforming the sulfur assimilation pathway MET3 , MET14 , MET16 , MET5 , MET10 and MET17 (Figure 7).…”

“…In that work, the laboratory strain S288c was used, which is genetically closer to WE lineage than to the WA. In addition, a recent report showed that PAT strongly induces the gene RPN2 , whose expression is known to be positively correlated with 20s proteasome activity; suggesting that PAT has a proteotoxic effect [44]. However, this gene was not among those DEGs either in the WE or WA strains.…”

Fungal Toxins and Host Immune Responses

“…Patulin is produced in a 10-step biosynthetic pathway that is controlled by 15 genes (Puel et al, 2010;Li et al, 2019). Mice that received an intraperitoneal injection of patulin (1 mg/kg body weight) exhibited a significant increase in the level of ROS in hepatic tissue (Song et al, 2014;Guerra-Moreno and Hanna, 2017;Sun et al, 2018) while 2 µM patulin induced autophagy in HepG2 liver cells in vitro (Sun et al, 2018), suggesting that patulin may have a detrimental impact on liver function in addition to immunotoxicity.…”