2. Academic Validation
  3. TSC2/mTORC1 integrates deoxynivalenol signals recognized by membrane receptors IR and EGFR to restrict intestinal stem cell function

TSC2/mTORC1 integrates deoxynivalenol signals recognized by membrane receptors IR and EGFR to restrict intestinal stem cell function

  • J Hazard Mater. 2025 Aug 15:494:138769. doi: 10.1016/j.jhazmat.2025.138769.
Cai-Xia Dou 1,  Hao-Zhan Qu 1,  Ying-Chao Qin 1,  Xiao-Fan Wang 1,  Hui-Chao Yan 1,  Run-Sheng Li 2,  Yu-Guang Zhao 3,  Jia-Yi Zhou 4,  Xiu-Qi Wang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Swine and Poultry Breeding Industry/College of Animal Science, South China Agricultural University/National Engineering Research Center for Breeding Swine Industry/Guangdong Laboratory for Lingnan Modern Agriculture/Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, 510642, China.
  • 2 Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, 999077, Hong Kong.
  • 3 Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
  • 4 State Key Laboratory of Swine and Poultry Breeding Industry/College of Animal Science, South China Agricultural University/National Engineering Research Center for Breeding Swine Industry/Guangdong Laboratory for Lingnan Modern Agriculture/Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, 510642, China. Electronic address: jyzhou@scau.edu.cn.
  • 5 State Key Laboratory of Swine and Poultry Breeding Industry/College of Animal Science, South China Agricultural University/National Engineering Research Center for Breeding Swine Industry/Guangdong Laboratory for Lingnan Modern Agriculture/Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, 510642, China. Electronic address: xqwang@scau.edu.cn.
PMID: 40466374 DOI: 10.1016/j.jhazmat.2025.138769
Abstract

Deoxynivalenol (DON) is a chemically stable mycotoxin with a slow natural degradation rate. Consumption of DON-contaminated food and feed poses significant health risks to human and livestock, leading to reduced productivity and substantial economic losses. The functionality of intestinal stem cells (ISCs) are compromised following sustained intracellular deoxynivalenol (DON) stress. Yet, it remains unclear how membrane receptors integrate extracellular DON to impair orderly ISC fate commitments. Here, we found that mechanistic target of rapamycin complex 1 (mTORC1), as well as its upstream signaling pathways such as Insulin, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase-Akt (PI3K/Akt), are involved in DON restraining ISC proliferation and differentiation to disrupt piglet jejunal epithelial structural integrity through single-cell RNA Sequencing (scRNA-seq). Using the ex vivo porcine intestinal Organoid and in vitro IPEC-J2 cell line, we identified that mTORC1 activation and tuberous sclerosis complex 2 (TSC2) knockout could repair DON-induced ISC injury. Furthermore, DON repressed the TSC2/mTORC1 upstream membrane receptors Insulin Receptor (IR) and epidermal growth factor receptor (EGFR); conversely, overexpression of IR or EGFR, especially co-overexpression of both, maintained the ISC regeneration in the presence of DON. Importantly, exothermic reactions between DON and the extracellular domains of IR/EGFR monitored by isothermal titration calorimetry (ITC) revealed a composite response consisting of DON recruitment and IR/EGFR conformational dynamics. Therefore, we have ascertained that the extracellular DON regulates intracellular TSC2/mTORC1 activity to restrict ISC function through the interaction with membrane receptors IR and EGFR.

Keywords

Deoxynivalenol; Insulin and epidermal growth factor receptors; Intestinal stem cells; Piglets; TSC2/mTOR signaling.

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