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Fumonisin B1 induces autophagic cell death via activation of ERN1-MAPK8/9/10 pathway in monkey kidney MARC-145 cells

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Abstract

Mycotoxins are secondary fungal metabolites that are capable of inducing a variety of toxic effects in animals and humans resulting from the consumption of the contaminated food. Understanding the mechanisms of the toxicities behind these mycotoxins is required to develop mechanism-based approach to counteract their toxic potential. Fumonisin B1 (FB1) is the most prevalent member of fumonisins that are a group of mycotoxins produced primarily by Fusarium verticillioides and Fusarium proliferatum. Kidney is one of the primary target organs for FB1 action. Using monkey kidney MARC-145 cells as an intro model, we found that FB1 induced caspase-independent programmed cell death accompanied with autophagy induction. Inhibition of autophagy by either chemical inhibitors or RNAi approach led to a significant reduction in cell death by FB1 exposure, indicating possible involvement of autophagy-mediated cell death in nephrotoxicity of FB1. Further mechanistic investigation revealed that activation of ERN1-MAPK8/9/10 axis played a critical role in autophagy induction and autophagy-mediated cell death by FB1 exposure. In addition, we demonstrated that disruption of sphingolipid metabolism was an apical event in FB1-induced ERN1-MAPK8/9/10-mediated autophagic cell death in MARC-145 cells. Lastly, we identified curcumin, a naturally occurring plant phenolic compound, as a possible anti-FB1 agent that can be used to protect kidney cells from FB1-induced cell death through inhibition of MAPK8/9/10 activation.

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Abbreviations

MAPKs:

Mitogen-activated protein kinases

ERN1:

Endoplasmic reticulum to nucleus signaling 1

ER:

Endoplasmic reticulum

mTOR:

Mammalian target of rapamycin

LC3:

Microtubule-associated protein 1 light chain 3

EIF2AK3:

Eukaryotic translation initiation factor 2-alpha kinase 3

EIF2S1:

Eukaryotic translation initiation factor 2, subunit 1 alpha

DDIT3:

DNA-damage-inducible transcript 3

EIF4EBP1:

Eukaryotic translation initiation factor 4E-binding protein 1

RPS6KB1:

Ribosomal protein S6 kinase

ATG7:

Autophagy-related 7

ACTB:

Actin, beta

FB1:

Fumonisin B1

CHX:

Cyclohexmide

3-MA:

3-Methyladenine

BAF:

Bafilomycin A1

DBS:

3-Ethoxy-5,6-dibromosalicylaldehyde

Nec-1:

Necrostatin-1

TEM:

Transmission electron microscopy

siRNA:

Small interfering RNA

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Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (NSFC, 31371752) and Ministry of Science and Technology of China (2012BAD33B09).

Conflict of interest

The authors have no conflicts of interest to disclosure.

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Authors and Affiliations

  1. Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, No 17 Qinghua East Road, Haidian District, Beijing, 100083, China

    Shutao Yin, Xiao Guo, Jinghua Li & Hongbo Hu

  2. College of Veterinary Medicine, China Agricultural University, No 2 Yunmingyuan West Road, Hiadian District, Beijing, 1000193, China

    Linghong Fan

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  1. Shutao Yin
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  2. Xiao Guo
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  3. Jinghua Li
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  4. Linghong Fan
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Correspondence to Linghong Fan or Hongbo Hu.

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Yin, S., Guo, X., Li, J. et al. Fumonisin B1 induces autophagic cell death via activation of ERN1-MAPK8/9/10 pathway in monkey kidney MARC-145 cells. Arch Toxicol 90, 985–996 (2016). https://doi.org/10.1007/s00204-015-1514-9

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