{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T21:02:42Z","timestamp":1791838962461,"version":"4.3.4"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2009,2,1]],"date-time":"2009-02-01T00:00:00Z","timestamp":1233446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 TCR\u03b6 protein levels. Pull-down studies revealed a direct interaction of HRES-1\/Rab4 with CD4 and TCR\u03b6. Importantly, the deficiency of the TCR\u03b6 chain and of Lck and the compensatory up-regulation of Fc\u03b5RI\u03b3 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 TCR\u03b6 protein levels in vitro. The results suggest that activation of mTOR causes the loss of TCR\u03b6 in lupus T cells through HRES-1\/Rab4-dependent lysosomal degradation.<\/jats:p>","DOI":"10.4049\/jimmunol.0803600","type":"journal-article","created":{"date-parts":[[2009,2,9]],"date-time":"2009-02-09T12:02:33Z","timestamp":1234180953000},"page":"2063-2073","source":"Crossref","is-referenced-by-count":247,"title":["Activation of Mammalian Target of Rapamycin Controls the Loss of TCR\u03b6 in Lupus T Cells through HRES-1\/Rab4-Regulated Lysosomal Degradation"],"prefix":"10.1093","volume":"182","author":[{"given":"David R","family":"Fernandez","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Department of Medicine"},{"name":"Department of Microbiology and Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Telarico","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine"},{"name":"Department of Microbiology and Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Bonilla","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank A","family":"Middleton","sequence":"additional","affiliation":[{"name":"Genetics Core, Department of Neuroscience and Physiology, State University of New York , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul E","family":"Phillips","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary K","family":"Crow","sequence":"additional","affiliation":[{"name":"Hospital for Special Surgery , New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Oess","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Frankfurt , Frankfurt,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Muller-Esterl","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Frankfurt , Frankfurt,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andras","family":"Perl","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine"},{"name":"Department of Microbiology and Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,2,15]]},"reference":[{"key":"2026012806242464000_R1","first-page":"123","article-title":"T and B cell abnormalities in systemic lupus erythematosus.","volume-title":"Crit. Rev. Immunol.","year":"2005"},{"key":"2026012806242464000_R2","first-page":"360","article-title":"Mitochondrial hyperpolarization: a checkpoint of T cell life, death, and autoimmunity.","volume-title":"Trends Immunol.","year":"2004"},{"key":"2026012806242464000_R3","first-page":"3685","article-title":"Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus.","volume-title":"J. Immunol.","year":"1994"},{"key":"2026012806242464000_R4","first-page":"1317","article-title":"Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes.","volume-title":"J. Exp. Med.","year":"1994"},{"key":"2026012806242464000_R5","first-page":"293","article-title":"Defective CD3-mediated cell death in activated T cells from patients with systemic lupus erythematosus: role of decreased intracellular TNF-\u03b1.","volume-title":"Clin. Immunol. Immunopathol.","year":"1996"},{"key":"2026012806242464000_R6","first-page":"175","article-title":"Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus.","volume-title":"Arthitis Rheum.","year":"2002"},{"key":"2026012806242464000_R7","first-page":"1092","article-title":"Persistent mitochondrial hyperpolarization, increased reactive oxygen intermediate production, and cytoplasmic alkalinization characterize altered IL-10 signaling in patients with systemic lupus erythematosus.","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012806242464000_R8","first-page":"3417","article-title":"Increased caspase-3 expression and activity contribute to reduced CD3\u03b6 expression in systemic lupus erythematosus T cells.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012806242464000_R9","first-page":"3364","article-title":"Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains.","volume-title":"Eur. J. Immunol.","year":"2005"},{"key":"2026012806242464000_R10","first-page":"548","article-title":"T lymphocytes in systemic lupus erythematosus: an update.","volume-title":"Curr. Opin. Rheumatol.","year":"2004"},{"key":"2026012806242464000_R11","first-page":"3676","article-title":"Nitric oxide-dependent mitochondrial biogenesis generates Ca2+ signaling profile of lupus T cells.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012806242464000_R12","first-page":"1948","article-title":"Reconstitution of deficient T cell receptor \u03b6 chain restores T cell signaling and augments T cell receptor\/CD3-induced interleukin-2 production in patients with systemic lupus erythematosus.","volume-title":"Arthritis Rheum.","year":"2003"},{"key":"2026012806242464000_R13","first-page":"705","article-title":"Systems biology in systemic lupus erythematosus: integrating genes, biology and immune function.","volume-title":"Autoimmunity","year":"2006"},{"key":"2026012806242464000_R14","first-page":"1114","article-title":"Fc\u03b5 receptor type I \u03b3 chain replaces the deficient T cell receptor \u03b6 chain in T cells of patients with systemic lupus erythematosus.","volume-title":"Arthritis Rheum.","year":"2001"},{"key":"2026012806242464000_R15","first-page":"4319","article-title":"FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2002"},{"key":"2026012806242464000_R16","first-page":"596","article-title":"Growing roles for the mTOR pathway.","volume-title":"Curr. Opin. Cell Biol.","year":"2005"},{"key":"2026012806242464000_R17","first-page":"381","article-title":"Rapamycin: something old, something new, sometimes borrowed and now renewed.","volume-title":"Clin. Pharmacol. 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Cell Biol.","year":"2004"},{"key":"2026012806242464000_R22","first-page":"735","article-title":"Rab conversion as a mechanism of progression from early to late endosomes.","volume-title":"Cell","year":"2005"},{"key":"2026012806242464000_R23","first-page":"8210","article-title":"Four additional members of the ras gene superfamily isolated by an oligonucleotide strategy: molecular cloning of YPT-related cDNAs from a rat brain library.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1987"},{"key":"2026012806242464000_R24","first-page":"34574","article-title":"Regulation of CD4 expression via recycling by HRES-1\/RAB4 controls susceptibility to HIV infection.","volume-title":"J. Biol. Chem.","year":"2006"},{"key":"2026012806242464000_R25","first-page":"809","article-title":"Dynamics of p56lck translocation to the T cell immunological synapse following agonist and antagonist stimulation.","volume-title":"Immunity","year":"2002"},{"key":"2026012806242464000_R26","first-page":"3140","article-title":"Tyrosine and serine protein kinase activities associated with ligand- induced internalized TCR\/CD3 complexes.","volume-title":"J. Immunol.","year":"1997"},{"key":"2026012806242464000_R27","first-page":"1675","article-title":"Transferrin receptor induces tyrosine phosphorylation in T cells and is physically associated with the TCR \u03b6-chain.","volume-title":"J. Immunol.","year":"1995"},{"key":"2026012806242464000_R28","first-page":"2276","article-title":"Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake.","volume-title":"Mol. Biol. Cell","year":"2002"},{"key":"2026012806242464000_R29","first-page":"5188","article-title":"T cell activation-induced mitochondrial hyperpolarization is mediated by Ca2+- and redox-dependent production of nitric oxide.","volume-title":"J. Immunol.","year":"2003"},{"key":"2026012806242464000_R30","first-page":"1271","article-title":"The 1982 revised criteria for the classification of systemic lupus erythematosus.","volume-title":"Arthritis Rheum.","year":"1982"},{"key":"2026012806242464000_R31","first-page":"630","article-title":"Derivation of the SLEDAI: a disease activity index for lupus patients.","volume-title":"Arthritis Rheum.","year":"1992"},{"key":"2026012806242464000_R32","first-page":"315","article-title":"The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.","volume-title":"Arthritis Rheum.","year":"1988"},{"key":"2026012806242464000_R33","first-page":"185","article-title":"Effector activity of OKT4+ and OKT8+ T cell subsets in lectin- dependent cell-mediated cytotoxicity against adherent HEp-2 cells.","volume-title":"Cell. Immunol.","year":"1984"},{"key":"2026012806242464000_R34","first-page":"14813","article-title":"Transaldolase is essential for maintenance of the mitochondrial transmembrane potential and fertility of spermatozoa.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2006"},{"key":"2026012806242464000_R35","first-page":"123","article-title":"Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing.","volume-title":"Biochem. J.","year":"2008"},{"key":"2026012806242464000_R36","first-page":"1906","article-title":"Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies.","volume-title":"Arthritis Rheum.","year":"2006"},{"key":"2026012806242464000_R37","first-page":"711","article-title":"Interferon and granulopoiesis signatures in systemic lupus erythematosus blood.","volume-title":"J. Exp. Med.","year":"2003"},{"key":"2026012806242464000_R38","first-page":"2610","article-title":"Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2003"},{"key":"2026012806242464000_R39","first-page":"3958","article-title":"Coordinate overexpression of interferon \u03b1-induced genes in systemic lupus erythematosus.","volume-title":"Arthritis Rheum.","year":"2004"},{"key":"2026012806242464000_R40","first-page":"227S","article-title":"Molecular actions of sirolimus: sirolimus and mTor.","volume-title":"Transplant. Proc.","year":"2003"},{"key":"2026012806242464000_R41","first-page":"729","article-title":"The small GTP-binding protein rab4 controls an early sorting event on the endocytic pathway.","volume-title":"Cell","year":"1992"},{"key":"2026012806242464000_R42","first-page":"39505","article-title":"Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex.","volume-title":"J. Biol. Chem.","year":"2005"},{"key":"2026012806242464000_R43","first-page":"675","article-title":"High doses of siRNAs induce eri-1 and adar-1 gene expression and reduce the efficiency of RNA interference in the mouse.","volume-title":"Biochem. J.","year":"2005"},{"key":"2026012806242464000_R44","first-page":"32280","article-title":"The interaction of Akt with APPL1 is required for insulin-stimulated Glut4 translocation.","volume-title":"J. Biol. Chem.","year":"2007"},{"key":"2026012806242464000_R45","first-page":"1748","article-title":"The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake.","volume-title":"Am. J. Pathol.","year":"2008"},{"key":"2026012806242464000_R46","first-page":"247","article-title":"Vpu-mediated degradation of CD4 reconstituted in yeast reveals mechanistic differences to cellular ER-associated protein degradation.","volume-title":"Mol. Cell","year":"2004"},{"key":"2026012806242464000_R47","first-page":"7821","article-title":"Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012806242464000_R48","first-page":"1176","article-title":"Altered lipid raft-associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus.","volume-title":"J. Clin. Invest.","year":"2004"},{"key":"2026012806242464000_R49","first-page":"1343","article-title":"Increased ubiquitination and reduced expression of LCK in T lymphocytes from patients with systemic lupus erythematosus.","volume-title":"Arthritis Rheum.","year":"2003"},{"key":"2026012806242464000_R50","first-page":"5981","article-title":"A model for antigen-specific T-cell anergy: displacement of CD4\u2013p56lck signalosome from the lipid rafts by a soluble, dimeric peptide-MHC class II chimera.","volume-title":"J. Immunol.","year":"2003"},{"key":"2026012806242464000_R51","first-page":"28827","article-title":"T cell receptor signaling: beyond complex complexes.","volume-title":"J. Biol. Chem.","year":"2004"},{"key":"2026012806242464000_R52","first-page":"48607","article-title":"The p85\u03b1 subunit of phosphatidylinositol 3\u2032-kinase binds to and stimulates the GTPase activity of Rab proteins.","volume-title":"J. Biol. Chem.","year":"2004"},{"key":"2026012806242464000_R53","first-page":"1859","article-title":"Degradation of T cell receptor (TCR)-CD3-\u03b6 complexes after antigenic stimulation.","volume-title":"J. Exp. Med.","year":"1997"},{"key":"2026012806242464000_R54","first-page":"1192","article-title":"c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation.","volume-title":"Nat. Immunol.","year":"2002"},{"key":"2026012806242464000_R55","first-page":"150","article-title":"A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus.","volume-title":"Immunity","year":"2008"},{"key":"2026012806242464000_R56","first-page":"1491","article-title":"Activation of the interferon \u03b1 pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease.","volume-title":"Arthritis Rheum.","year":"2005"},{"key":"2026012806242464000_R57","first-page":"1466","article-title":"Elevation of mitochondrial transmembrane potential and reactive oxygen intermediate levels are early events and occur independently from activation of caspases in Fas signaling.","volume-title":"J. Immunol.","year":"1999"},{"key":"2026012806242464000_R58","first-page":"119","article-title":"Unraveling the genetics of systemic lupus erythematosus.","volume-title":"Springer Semin. Immunpathol.","year":"2006"},{"key":"2026012806242464000_R59","first-page":"14869","article-title":"Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1998"},{"key":"2026012806242464000_R60","first-page":"230","article-title":"Chromosome 17p12\u2013q11 harbors susceptibility loci for systemic lupus erythematosus.","volume-title":"Hum. Genet.","year":"2004"},{"key":"2026012806242464000_R61","first-page":"169","article-title":"A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q.","volume-title":"J. Autoimmun.","year":"2000"},{"key":"2026012806242464000_R62","first-page":"725","article-title":"Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus.","volume-title":"J. Clin. Invest.","year":"1997"},{"key":"2026012806242464000_R63","first-page":"14875","article-title":"A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1998"},{"key":"2026012806242464000_R64","first-page":"1135","article-title":"PARP alleles with the linked chromosomal region are associated with systemic lupus erythematosus.","volume-title":"J. Clin. Invest.","year":"1999"},{"key":"2026012806242464000_R65","first-page":"639","article-title":"Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families.","volume-title":"Hum. Mol. Genet.","year":"1999"},{"key":"2026012806242464000_R66","first-page":"1172","article-title":"The human T cell leukemia virus-related endogenous sequence (HRES1) is located on chromosome 1 at q42.","volume-title":"Genomics","year":"1991"},{"key":"2026012806242464000_R67","first-page":"S316","article-title":"Mapping and cloning of polymorphic genotypes of the HRES-1 LTR.","volume-title":"Arthritis Rheum.","year":"1994"},{"key":"2026012806242464000_R68","first-page":"829","article-title":"Polymorphic genotypes of the HRES-1 human endogenous retrovirus locus correlate with systemic lupus erythematosus and autoreactivity.","volume-title":"Immunogenetics","year":"1999"},{"key":"2026012806242464000_R69","first-page":"532","article-title":"Haplotypes of the HRES-1 endogenous retrovirus are associated with development and disease manifestations of systemic lupus erythematosus.","volume-title":"Arthritis Rheum.","year":"2008"},{"key":"2026012806242464000_R70","first-page":"342","article-title":"Ribosomal protein S6 phosphorylation: from protein synthesis to cell size.","volume-title":"Trends Biochem. 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