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

Isamu Sakabe, Rong Hu, Lu Jin, Robert Clarke, Usha N. Kasid

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)285-297
Number of pages13
JournalBreast Cancer Research and Treatment
Issue number2
StatePublished - Sep 7 2015
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. Sona Vasudevan for analysis of TMEM33 profiles in The Cancer Genome Atlas (TCGA) and cBioPortal databases. This work was funded by NIH Grants CA68322, CA74175, CA149147, and CA184902 and NeoPharm, Inc. Several cell lines were obtained from the Tissue Culture Shared Resource of the Georgetown Lombardi Cancer Center. The RNA array expression profiling was performed at the Genomics and Epigenomics Shared Resource and the immunofluorescence imaging was performed at the Microscopy & Imaging Shared Resource of the Georgetown Lombardi Cancer Center. All shared resources were supported by the NIH Grant P30-CA51008.

Publisher Copyright:
© 2015, The Author(s).


  • Autophagy
  • Breast cancer
  • Caspase-7
  • Endoplasmic reticulum stress and unfolded protein response
  • IRE1α
  • PERK
  • TMEM33


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