title: The involvement of SMILE/TMTC3 in endoplasmic reticulum stress response.
abstract: BACKGROUND
  The state of operational tolerance has been detected sporadically in some renal transplanted patients that stopped immunosuppressive drugs, demonstrating that allograft tolerance might exist in humans. Several years ago, a study by Brouard et al. identified a molecular signature of several genes that were significantly differentially expressed in the blood of such patients compared with patients with other clinical situations. The aim of the present study is to analyze the role of one of these molecules over-expressed in the blood of operationally tolerant patients, SMILE or TMTC3, a protein whose function is still unknown.
  
  
  RESULTS
  We first confirmed that SMILE mRNA is differentially expressed in the blood of operationally tolerant patients with drug-free long term graft function compared to stable and rejecting patients. Using a yeast two-hybrid approach and a colocalization study by confocal microscopy we furthermore report an interaction of SMILE with PDIA3, a molecule resident in the endoplasmic reticulum (ER). In accordance with this observation, SMILE silencing in HeLa cells correlated with the modulation of several transcripts involved in proteolysis and a decrease in proteasome activity. Finally, SMILE silencing increased HeLa cell sensitivity to the proteasome inhibitor Bortezomib, a drug that induces ER stress via protein overload, and increased transcript expression of a stress response protein, XBP-1, in HeLa cells and keratinocytes.
  
  
  CONCLUSIONS
  In this study we showed that SMILE is involved in the endoplasmic reticulum stress response, by modulating proteasome activity and XBP-1 transcript expression. This function of SMILE may influence immune cell behavior in the context of transplantation, and the analysis of endoplasmic reticulum stress in transplantation may reveal new pathways of regulation in long-term graft acceptance thereby increasing our understanding of tolerance.
authors: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche 643, Nantes, France.
authors: Maud
authors: M
authors: Racapé
authors: Jean-Paul
authors: JP
authors: Duong Van Huyen
authors: Richard
authors: R
authors: Danger
authors: Magali
authors: M
authors: Giral
authors: Françoise
authors: F
authors: Bleicher
authors: Yohann
authors: Y
authors: Foucher
authors: Annaïck
authors: A
authors: Pallier
authors: Paul
authors: P
authors: Pilet
authors: Petra
authors: P
authors: Tafelmeyer
authors: Joanna
authors: J
authors: Ashton-Chess
authors: Emilie
authors: E
authors: Dugast
authors: Ségolène
authors: S
authors: Pettré
authors: Béatrice
authors: B
authors: Charreau
authors: Jean-Paul
authors: JP
authors: Soulillou
authors: Sophie
authors: S
authors: Brouard
references: Methods Enzymol. 1995;255:331-42
references: 8524119
references: Am J Transplant. 2010 Mar;10(3):464-71
references: 20121738
references: J Clin Invest. 2010 Jun;120(6):1836-47
references: 20501946
references: N Engl J Med. 2005 Mar 31;352(13):1371-3
references: 15800234
references: J Mol Cell Cardiol. 2008 Aug;45(2):250-60
references: 18586265
references: J Hepatol. 2009 Jun;50(6):1247-57
references: 19394103
references: Transpl Int. 2007 Oct;20(10):828-41
references: 17711408
references: J Immunol. 2010 Aug 15;185(4):2324-30
references: 20660350
references: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references: 11309499
references: J Clin Invest. 2010 Jun;120(6):1848-61
references: 20501943
references: Hum Immunol. 2010 May;71(5):442-50
references: 20122976
references: EMBO J. 2005 Oct 5;24(19):3470-81
references: 16148948
references: Nat Immunol. 2003 Apr;4(4):321-9
references: 12612580
references: Cell Stress Chaperones. 2010 May;15(3):281-93
references: 19898960
references: Nature. 2008 Jul 24;454(7203):455-62
references: 18650916
references: Genome Res. 2005 Mar;15(3):376-84
references: 15710747
references: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15448-53
references: 17873064
references: Transplantation. 2009 Sep 15;88(5):605-13
references: 19741454
references: Am J Transplant. 2008 Nov;8(11):2283-96
references: 18785955
references: Kidney Int. 2010 Sep;78(5):503-13
references: 20531452
references: J Exp Med. 2005 Aug 15;202(4):505-16
references: 16103408
references: J Am Soc Nephrol. 2008 Nov;19(11):2225-36
references: 18776125
references: J Exp Med. 2007 Oct 1;204(10):2267-75
references: 17875675
references: J Biol Chem. 2009 Dec 11;284(50):35134-43
references: 19826008
references: Annu Rev Biochem. 2005;74:739-89
references: 15952902
references: J Biol Chem. 2007 Jun 15;282(24):17587-93
references: 17459881
references: Trends Biochem Sci. 2001 Aug;26(8):504-10
references: 11504627
references: Am J Transplant. 2006 Apr;6(4):736-46
references: 16539630
references: Cancer Res. 2008 Nov 15;68(22):9323-30
references: 19010906
references: Am J Transplant. 2009 Sep;9(9):2126-35
references: 19624570
references: Genome Biol. 2004;5(10):R80
references: 15461798
references: Blood. 2006 Jun 15;107(12):4907-16
references: 16507771
references: Bioessays. 1999 Nov;21(11):932-9
references: 10517866
references: J Exp Med. 2009 Sep 28;206(10):2151-9
references: 19752183
references: Transplantation. 2006 Feb 15;81(3):398-407
references: 16477227
references: Genome Biol. 2003;4(4):R28
references: 12702209
references: Calcif Tissue Int. 2000 Feb;66(2):129-38
references: 10652961
references: Transplantation. 2010 Jul 27;90(2):221-2
references: 20644455
references: Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17698-703
references: 20876114
references: Nat Cell Biol. 2001 Nov;3(11):E255-63
references: 11715037
references: Nat Genet. 1997 Jul;16(3):277-82
references: 9207794
references: Transplantation. 2009 May 27;87(10):1555-61
references: 19461494
references: Lab Invest. 2009 Mar;89(3):327-36
references: 19139722
references: N Engl J Med. 2008 Jan 24;358(4):353-61
references: 18216355