Regulation of Enterocyte Apoptosis by Acyl-CoA Synthetase 5 Splicing

Tobias Longin Haas, Nikolaus Gassler, Wilfried Roth, Benjamin Funke, Armin Schneider, Frank Herzog, Jens J.W. Tischendorf, Kerstin Grund, Roland Penzel, Ignacio G. Bravo, John Mariadason, Volker Ehemann, Jaromir Sykora, Henning Walczak, Tom Ganten, Hanswalter Zentgraf, Peter Erb, Angel Alonso, Frank Autschbach, Peter SchirmacherRuth Knüchel, Jürgen Kopitz

Risultato della ricerca: Contributo in rivistaArticolo in rivista

40 Citazioni (Scopus)

Abstract

Background & Aims: The constant renewal of enterocytes along the crypt-villus axis (CVA) of human small intestine is due to cell-inherent changes resulting in the apoptotic cell death of senescent enterocytes. The aim of the present study was to examine underlying molecular mechanisms of the cell death at the villus tip. Methods: Characterization of human acyl-coenzyme A (CoA) synthetase 5 (ACSL5) was performed by cloning, recombinant protein expression, biochemical approaches, and several functional and in situ analyses. Results: Our data show that different amounts of acyl-CoA synthetase 5-full length (ACSL5-fl) and a so far unknown splice variant lacking exon 20 (ACSL5-Δ20) are found in human enterocytes. In contrast with the splice variant ACSL5-Δ20, recombinant and purified ACSL5-fl protein is active at a highly alkaline pH. Over expression of ACSL5-fl protein is associated with a decrease of the anti-apoptotic FLIP protein in a ceramide-dependent manner and an increased cell-surface expression of the death receptor TRAIL-R1. Expression analyses revealed that the ACSL5-fl/ACSL5-Δ20 ratio increases along the CVA, thereby sensitizing ACSL5-fl-dominated cells at the villus tip to the death ligand TRAIL, which is corroborated by functional studies with human small intestinal mucosal samples and an immortalized human small intestinal cell line. Conclusions: Our results suggest an ACSL5-dependent regulatory mechanism that contributes to the cellular renewal along the CVA in human small intestine. Deregulation of the ACSL5-fl/ACSL5-Δ20 homeostasis in the maturation and shedding of cells along the CVA might also be of relevance for the development of intestinal neoplasia. © 2007 AGA Institute.
Lingua originaleEnglish
pagine (da-a)587-598
Numero di pagine12
RivistaGastroenterology
Volume133
DOI
Stato di pubblicazionePubblicato - 2007

Keywords

  • Aged
  • Alternative Splicing
  • Amino Acid Sequence
  • Apoptosis
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Caco-2 Cells
  • Caspase 3
  • Celiac Disease
  • Ceramides
  • Coenzyme A Ligases
  • Duodenum
  • Endoplasmic Reticulum
  • Enterocytes
  • Enzyme Activation
  • Gastroenterology
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Hydrogen-Ion Concentration
  • Ileum
  • Microvilli
  • Middle Aged
  • Mitochondria
  • Molecular Sequence Data
  • RNA, Messenger
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • Transfection

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