Dextran Sodium Sulfate-Induced Impairment of Protein Trafficking and Alterations in Membrane Composition in Intestinal Caco-2 Cell Line

Int J Mol Sci. 2020 Apr 15;21(8):2726. doi: 10.3390/ijms21082726.


A key morphological feature of inflammatory bowel disease (IBD) is the loss of the barrier function of intestinal epithelial cells. The present study investigates endoplasmic reticulum (ER) stress in addition to alterations in protein and membrane trafficking in a dextran sulfate sodium (DSS)-induced IBD-like phenotype of intestinal Caco-2 cells in culture. DSS treatment significantly reduced the transepithelial electric resistance (TEER) and increased the epithelial permeability of Caco-2 cells, without affecting their viability. This was associated with an alteration in the expression levels of inflammatory factors in addition to an increase in the expression of the ER stress protein markers, namely immunoglobulin-binding protein (BiP), C/EBP homologous protein (CHOP), activation transcription factor 4 (ATF4), and X-box binding protein (XBP1). The DSS-induced ER-stress resulted in impaired intracellular trafficking and polarized sorting of sucrase-isomaltase (SI) and dipeptidyl peptidase-4 (DPPIV), which are normally sorted to the apical membrane via association with lipid rafts. The observed impaired sorting was caused by reduced cholesterol levels and subsequent distortion of the lipid rafts. The data presented confirm perturbation of ER homeostasis in DSS-treated Caco-2 cells, accompanied by impairment of membrane and protein trafficking resulting in altered membrane integrity, cellular polarity, and hence disrupted barrier function.

Keywords: anti- and pro-inflammatory cytokines; brush border membranes; cholesterol; dipeptidyl peptidase-4; endoplasmic reticulum stress; inflammatory bowel disease; lipid rafts; sucrase-isomaltase.

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Bacterial Proteins / metabolism
  • Caco-2 Cells
  • Cell Death / drug effects
  • Cell Membrane / chemistry
  • Cell Membrane / drug effects
  • Cell Membrane / enzymology
  • Cell Membrane / metabolism*
  • Cell Membrane Permeability / drug effects*
  • Cell Polarity / drug effects
  • Cell Survival / drug effects
  • Cholesterol / metabolism
  • Cytokines / metabolism
  • Dextran Sulfate / toxicity*
  • Dipeptidyl Peptidase 4 / metabolism
  • Endoplasmic Reticulum Stress / drug effects*
  • Epithelial Cells / drug effects*
  • Epithelial Cells / enzymology
  • Epithelial Cells / metabolism
  • Epithelial Cells / physiology
  • Humans
  • Inflammatory Bowel Diseases / chemically induced
  • Inflammatory Bowel Diseases / enzymology
  • Inflammatory Bowel Diseases / metabolism*
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / pathology
  • Membrane Microdomains / chemistry
  • Membrane Microdomains / drug effects
  • Membrane Microdomains / metabolism
  • Protein Transport / drug effects
  • Sucrase-Isomaltase Complex / metabolism
  • Transcription Factor CHOP / metabolism
  • X-Box Binding Protein 1 / metabolism
  • alpha-Glucosidases / metabolism


  • ATF4 protein, human
  • Bacterial Proteins
  • Cytokines
  • DDIT3 protein, human
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • Dextran Sulfate
  • Cholesterol
  • Sucrase-Isomaltase Complex
  • sucrase-isomaltase-maltase
  • alpha-Glucosidases
  • Dipeptidyl Peptidase 4