PMID- 19201859
OWN - NLM
STAT- MEDLINE
DCOM- 20090304
LR  - 20230815
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 182
IP  - 4
DP  - 2009 Feb 15
TI  - Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus 
      T cells through HRES-1/Rab4-regulated lysosomal degradation.
PG  - 2063-73
LID - 10.4049/jimmunol.0803600 [doi]
AB  - Persistent mitochondrial hyperpolarization (MHP) and enhanced calcium fluxing 
      underlie aberrant T cell activation and death pathway selection in systemic lupus 
      erythematosus. Treatment with rapamycin, which effectively controls disease 
      activity, normalizes CD3/CD28-induced calcium fluxing but fails to influence MHP, 
      suggesting that altered calcium fluxing is downstream or independent of 
      mitochondrial dysfunction. In this article, we show that activity of the 
      mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial 
      transmembrane potential, is increased in lupus T cells. Activation of mTOR was 
      inducible by NO, a key trigger of MHP, which in turn enhanced the expression of 
      HRES-1/Rab4, a small GTPase that regulates recycling of surface receptors through 
      early endosomes. Expression of HRES-1/Rab4 was increased in CD4(+) lupus T cells, 
      and in accordance with its dominant impact on the endocytic recycling of CD4, it 
      was inversely correlated with diminished CD4 expression. HRES-1/Rab4 
      overexpression was also inversely correlated with diminished TCRzeta protein 
      levels. Pull-down studies revealed a direct interaction of HRES-1/Rab4 with CD4 
      and TCRzeta. Importantly, the deficiency of the TCRzeta chain and of Lck and the 
      compensatory up-regulation of FcepsilonRIgamma and Syk, which mediate enhanced 
      calcium fluxing in lupus T cells, were reversed in patients treated with 
      rapamcyin in vivo. Knockdown of HRES-1/Rab4 by small interfering RNA and 
      inhibitors of lysosomal function augmented TCRzeta protein levels in vitro. The 
      results suggest that activation of mTOR causes the loss of TCRzeta in lupus T 
      cells through HRES-1/Rab4-dependent lysosomal degradation.
FAU - Fernandez, David R
AU  - Fernandez DR
AD  - Division of Rheumatology, Department of Medicine, State University of New York, 
      Syracuse, NY 13210, USA.
FAU - Telarico, Tiffany
AU  - Telarico T
FAU - Bonilla, Eduardo
AU  - Bonilla E
FAU - Li, Qing
AU  - Li Q
FAU - Banerjee, Sanjay
AU  - Banerjee S
FAU - Middleton, Frank A
AU  - Middleton FA
FAU - Phillips, Paul E
AU  - Phillips PE
FAU - Crow, Mary K
AU  - Crow MK
FAU - Oess, Stefanie
AU  - Oess S
FAU - Muller-Esterl, Werner
AU  - Muller-Esterl W
FAU - Perl, Andras
AU  - Perl A
LA  - eng
GR  - R01 AI048079-02/AI/NIAID NIH HHS/United States
GR  - R56 AI048079-06/AI/NIAID NIH HHS/United States
GR  - AI-072648/AI/NIAID NIH HHS/United States
GR  - R01 AI048079-05/AI/NIAID NIH HHS/United States
GR  - R01 AI-048079/AI/NIAID NIH HHS/United States
GR  - R56 AI048079/AI/NIAID NIH HHS/United States
GR  - R01 AI048079-04/AI/NIAID NIH HHS/United States
GR  - R01 AI072648-01A2/AI/NIAID NIH HHS/United States
GR  - R01 AI048079-03/AI/NIAID NIH HHS/United States
GR  - R01 AI048079-01/AI/NIAID NIH HHS/United States
GR  - R21 AI061066-01/AI/NIAID NIH HHS/United States
GR  - R01 AI048079/AI/NIAID NIH HHS/United States
GR  - R21 AI061066/AI/NIAID NIH HHS/United States
GR  - R01 AI072648/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (antigen T cell receptor, zeta chain)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (rab4 GTP-Binding Proteins)
RN  - EC 3.6.5.2 (rab5 GTP-Binding Proteins)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Blotting, Western
MH  - CD4-Positive T-Lymphocytes/drug effects/*immunology/metabolism
MH  - Female
MH  - Flow Cytometry
MH  - Gene Expression/drug effects
MH  - Humans
MH  - Immunosuppressive Agents/therapeutic use
MH  - Lupus Erythematosus, Systemic/genetics/*immunology/metabolism
MH  - Microscopy, Confocal
MH  - Middle Aged
MH  - Nitric Oxide/metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - Protein Kinases/*immunology/metabolism
MH  - RNA, Small Interfering
MH  - Receptors, Antigen, T-Cell/*immunology/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Sirolimus/therapeutic use
MH  - TOR Serine-Threonine Kinases
MH  - Transfection
MH  - rab4 GTP-Binding Proteins/*immunology/metabolism
MH  - rab5 GTP-Binding Proteins/biosynthesis
PMC - PMC2676112
MID - NIHMS82451
EDAT- 2009/02/10 09:00
MHDA- 2009/03/05 09:00
PMCR- 2010/02/15
CRDT- 2009/02/10 09:00
PHST- 2009/02/10 09:00 [entrez]
PHST- 2009/02/10 09:00 [pubmed]
PHST- 2009/03/05 09:00 [medline]
PHST- 2010/02/15 00:00 [pmc-release]
AID - 182/4/2063 [pii]
AID - 10.4049/jimmunol.0803600 [doi]
PST - ppublish
SO  - J Immunol. 2009 Feb 15;182(4):2063-73. doi: 10.4049/jimmunol.0803600.