Transmembrane Protein 214 (TMEM214) mediates endoplasmic reticulum stress-induced caspase 4 enzyme activation and apoptosis

J Biol Chem. 2013 Jun 14;288(24):17908-17. doi: 10.1074/jbc.M113.458836. Epub 2013 May 9.

Abstract

Endoplasmic reticulum (ER) stress caused by excessive aggregation of misfolded proteins induces apoptosis. Although ER stress-induced apoptosis has been implicated in many diseases, the detailed mechanisms are not well understood. Here, we identified human transmembrane protein 214 (TMEM214) as a critical mediator of ER stress-induced apoptosis. Overexpression of TMEM214 induced apoptosis, whereas knockdown of TMEM214 inhibited ER stress-induced apoptosis. TMEM214 was localized on the outer membrane of the ER and constitutively associated with procaspase 4, which was also critical for ER stress-induced apoptosis. TMEM214-induced apoptosis was abolished by a dominant negative mutant of procaspase 4, whereas caspase 4-induced apoptosis was inhibited by knockdown of TMEM214. Furthermore, knockdown of TMEM214 inhibited the activation and cleavage of procaspase 4 by impairing its recruitment to the ER. Our findings suggest that TMEM214 is essential for ER stress-induced apoptosis by acting as an anchor for recruitment of procaspase 4 to the ER and its subsequent activation.

Keywords: Apoptosis; Caspase; Caspase 4; Cell Signaling; ER Stress; TMEM214; Unfolded Protein Response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Caspase 7 / metabolism
  • Caspases, Initiator / metabolism*
  • Cell Line, Tumor
  • Endoplasmic Reticulum / enzymology
  • Endoplasmic Reticulum Stress*
  • Enzyme Activation
  • Enzyme Precursors / metabolism*
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Intracellular Membranes / enzymology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Peptide Mapping
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • RNA Interference

Substances

  • Enzyme Precursors
  • Membrane Proteins
  • transmembrane protein 214, human
  • CASP4 protein, human
  • CASP7 protein, human
  • Caspase 7
  • Caspases, Initiator