ArticleJournal of immunology (Baltimore, Md. : 1950)2009
Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation.
Article in Journal of immunology (Baltimore, Md. : 1950), 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 151 papers, 4 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
151 citing papers in PubMed, 4 syntheses or guidelines pooled it, 251 citations in OpenAlex.
- Pooled it
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- A meta-analysis of public microarray data identifies gene regulatory pathways deregulated in peripheral blood mononuclear cells from individuals with Systemic Lupus Erythematosus compared to those without.BMC medical genomics · 2016Pooled it
- Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).Autophagy · 2016Guideline
- Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.Lancet (London, England) · 2018Trial
- N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.Arthritis and rheumatism · 2012Trial
- RAB4A acts as a negative feedback regulator of extracellular vesicle secretion during TGF-β signaling.The FEBS journal · 2026Article
- T-Cell Immunosenescence in Systemic Lupus Erythematosus: Molecular Mechanisms and Therapeutic Perspectives.Clinical reviews in allergy & immunology · 2026Review
- Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus.JCI insight · 2026Article
- Targeting ST18-mediated pathomechanism in pemphigus vulgaris through voltage-dependent anion channel inhibition.Skin health and disease · 2026Article
- Rab4 spatially and functionally converges with Rab7 in the degradative endolysosomal network.Molecular biology of the cell · 2026Article
- Endosome traffic in rheumatic diseases: mechanistic insights and therapeutic opportunities.Nature reviews. Rheumatology · 2026Review
- Targeting mTOR in Systemic Lupus Erythematosus: From Immune Cell Dysfunction to Clinical Translation.Journal of inflammation research · 2026Review
- Mitochondrial DNA in systemic lupus erythematosus: pathogenic mechanisms, clinical biomarkers, and precision therapeutic strategies.Frontiers in immunology · 2026Review
- Urinary 8-oxoGuo as a potential novel evaluation biomarker for patients with systemic lupus erythematosus.Clinical and experimental medicine · 2025Article
- Pathogenic drivers of lupus myocarditis and potential therapeutic targets.Experimental & molecular medicine · 2025Review
- Unveiling Molecular Mechanisms Underlying Obesity-Associated Systemic Lupus Erythematosus.Endocrinology, diabetes & metabolism · 2025Review
- Immunometabolism in systemic lupus erythematosus.Nature reviews. Rheumatology · 2025Review
- RAB4A DRIVES PROINFLAMMATORY CD4Research square · 2025Article
- Review
91 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.