TMEM33: a new stress-inducible endoplasmic reticulum transmembrane protein and modulator of the unfolded protein response signaling

Breast Cancer Res Treat. 2015 Sep;153(2):285-97. doi: 10.1007/s10549-015-3536-7. Epub 2015 Aug 13.


Endoplasmic reticulum (ER) stress leads to activation of the unfolded protein response (UPR) signaling cascade and induction of an apoptotic cell death, autophagy, oncogenesis, metastasis, and/or resistance to cancer therapies. Mechanisms underlying regulation of ER transmembrane proteins PERK, IRE1α, and ATF6α/β, and how the balance of these activities determines outcome of the activated UPR, remain largely unclear. Here, we report a novel molecule transmembrane protein 33 (TMEM33) and its actions in UPR signaling. Immunoblotting and northern blot hybridization assays were used to determine the effects of ER stress on TMEM33 expression levels in various cell lines. Transient transfections, immunofluorescence, subcellular fractionation, immunoprecipitation, and immunoblotting were used to study the subcellular localization of TMEM33, the binding partners of TMEM33, and the expression of downstream effectors of PERK and IRE1α. Our data demonstrate that TMEM33 is a unique ER stress-inducible and ER transmembrane molecule, and a new binding partner of PERK. Exogenous expression of TMEM33 led to increased expression of p-eIF2α and p-IRE1α and their known downstream effectors, ATF4-CHOP and XBP1-S, respectively, in breast cancer cells. TMEM33 overexpression also correlated with increased expression of apoptotic signals including cleaved caspase-7 and cleaved PARP, and an autophagosome protein LC3II, and reduced expression of the autophagy marker p62. TMEM33 is a novel regulator of the PERK-eIE2α-ATF4 and IRE1-XBP1 axes of the UPR signaling. Therefore, TMEM33 may function as a determinant of the ER stress-responsive events in cancer cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Amino Acid Sequence
  • Animals
  • Autophagy / genetics
  • Base Sequence
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum Stress
  • Endoribonucleases / metabolism
  • Eukaryotic Initiation Factor-2 / metabolism
  • Female
  • Gene Expression
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Molecular Sequence Data
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombinant Fusion Proteins
  • Regulatory Factor X Transcription Factors
  • Signal Transduction*
  • Transcription Factors / metabolism
  • Unfolded Protein Response*
  • X-Box Binding Protein 1
  • eIF-2 Kinase / metabolism


  • DNA-Binding Proteins
  • Eukaryotic Initiation Factor-2
  • Membrane Proteins
  • Recombinant Fusion Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • transmembrane protein 33, human
  • Activating Transcription Factor 4
  • EIF2AK3 protein, human
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases