Cited by 224T-cell and B-cell ImmunologyUbiquitin and proteasome pathwaysImmune Response and Inflammation

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E3 ubiquitin ligases as T cell anergy factors

Mueller, Daniel L·2004·Nature Immunology

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Abstract

E3 ubiquitin ligases have emerged as key molecular regulators of immune cell function. Three families of proteins with ubiquitin ligase activity have been described (the HECT, RING and U-box proteins), and each may be involved in the regulation of immune responses during infection by targeting specific inhibitory molecules for proteolytic destruction. Several HECT and RING E3 proteins have now also been linked to the induction and maintenance of immune self-tolerance: c-Cbl, Cbl-b, GRAIL, Itch and Nedd4 each negatively regulate T cell growth factor production and proliferation. This review will discuss the relationship between the ubiquitination of select components of the antigen-sensing signaling apparatus in T cells and the development and maintenance of the clonal anergy state.

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Background
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Background
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Background
A novel negative regulatory function of the phosphoprotein associated with glycosphingolipid-enriched microdomains: blocking Ras activation
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Fasciola hepatica tegumental antigens induce anergic‐like T cells via dendritic cells in a mannose receptor‐dependent manner
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UBD, a downstream element of FOXP3, allows the identification of LGALS3, a new marker of human regulatory T cells
Ocklenburg, F., Moharregh-Khiabani, D., Geffers, R., Janke, V., Pfoertner, S., Garritsen, H., Groebe, L., Klempnauer, J., Dittmar, K. E. J., Weiß, S., et al. (2006) · Laboratory Investigation · doi:10.1038/labinvest.3700432 · Cited by 60
“Proteins involved in ubiquitinylation play an important role in the regulation of T-cell anergy”
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T-Cell Tolerance in Cancer
Nurieva, R., Wang, J., & Sahoo, A. (2013) · Immunotherapy · doi:10.2217/imt.13.33 · Cited by 62
Cutting Edge: The Transmembrane E3 Ligase GRAIL Ubiquitinates the Costimulatory Molecule CD40 Ligand during the Induction of T Cell Anergy
Lineberry, N. B., Su, L., Lin, J. T., Coffey, G., Seroogy, C. M., & Fathman, C. G. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.3.1622 · Cited by 56
“Whereas early molecular research into clonal T cell anergy suggested defects in signaling proteins and transcription factors, the role of protein stability controlled by the ubiquitin-proteasome pathway in anergy induction and peripheral tolerance has recently been investigated (3, 4).”
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Activation-induced non-responsiveness (anergy) limits CD8 T cell responses to tumors
Mescher, M. F., Popescu, F. E., Gerner, M. Y., Hammerbeck, C. D., & Curtsinger, J. (2007) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2007.06.008 · Cited by 55
“Several E3 ubiquitin ligases have been implicated as acting as repressors that can limit IL-2 production and proliferation of CD4 T cells by altering components of the TCR/CD28 signaling pathways (reviewed in [42]).”
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Goliath family E3 ligases regulate the recycling endosome pathway via VAMP3 ubiquitylation
Yamazaki, Y., Schönherr, C., Varshney, G. K., Dogru, M., Hallberg, B., & Palmer, R. H. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.1 · Cited by 55
“Most functional information comes from studies of mammalian GRAIL/RNF128, which plays a role in immune tolerance (Mueller, 2004).”
The HECT-Type E3 Ubiquitin Ligase AIP2 Inhibits Activation-Induced T-Cell Death by Catalyzing EGR2 Ubiquitination
Chen, A., Gao, B., Zhang, J., McEwen, T. J., Ye, S. Q., Zhang, D. D., & Fang, D. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00407-09 · Cited by 51
“In addition, EGR2 regulates the development and activation of T lymphocytes in mice (32).”
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USP38 critically promotes asthmatic pathogenesis by stabilizing JunB protein
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“Some E3 ubiquitin ligases, including Cbl family, GRA IL, and Itch, play critical roles in T cell anergy and tolerance by regulating ubiquitination and degradation of key TCR signaling components (Heissmeyer et al., 2004; Mueller, 2004; Nurieva et al., 2010; Venuprasad, 2010).”
Cbl-b Regulates Antigen-Induced TCR Down-Regulation and IFN-γ Production by Effector CD8 T Cells without Affecting Functional Avidity
Shamim, M. H., Nanjappa, S. G., Singh, A., Plisch, E. H., LeBlanc, S. E., Walent, J. H., Svaren, J. P., Seroogy, C. M., & Suresh, M. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.11.7233 · Cited by 48
Naive CD4 T Cell Proliferation Is Controlled by Mammalian Target of Rapamycin Regulation of GRAIL Expression
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E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination
Zhao, Y., Guo, H., Qiao, G., Zucker, M., Langdon, W. Y., & Zhang, J. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1402434 · Cited by 47
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Ubiquitination system and autoimmunity: The bridge towards the modulation of the immune response
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ZAP70, too little, too much can lead to autoimmunity*
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Integrating human omics data to prioritize candidate genes
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“RNF128 encodes a type I transmembrane protein located in the endocytic pathway and its expression significantly inhibited activation-induced IL4 and IL2 [61] that are involved in type I diabetes mellitus pathway (KEGG: hsa04940).”
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Regulation of peripheral T cell tolerance by the E3 ubiquitin ligase Cbl-b
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Up-Regulation of Gene Related to Anergy in Lymphocytes Is Associated with Notch-Mediated Human T Cell Suppression
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“Cbl-b and Itch, also members of the E3 ubiquitin ligases family, have also been linked to anergy (20, 21).”
Background
Transcriptional regulation of T cell tolerance
Bandyopadhyay, S., Soto-Nieves, N., & Macián, F. (2007) · Seminars in Immunology · doi:10.1016/j.smim.2007.02.006 · Cited by 44
Cutting Edge: Requirement for TRAF6 in the Induction of T Cell Anergy
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RNF13: an emerging RING finger ubiquitin ligase important in cell proliferation
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“The expression of lamina-associated polypeptide 2 isoforms also known as thymopoetin, E3 ubiquitin-protein ligase, SAM and SH3 domain containing protein 1, and myelin and lymphocyte protein were also regulated and have been implicated in mammalian T-cell development [38–40].”
Background
The Sts proteins target tyrosine phosphorylated, ubiquitinated proteins within TCR signaling pathways
Carpino, N., Chen, Y., Nassar, N. N., & Oh, H.-W. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2009.08.015 · Cited by 40
Control of Virus-Specific CD8+T-Cell Exhaustion and Immune-Mediated Pathology by E3 Ubiquitin Ligase Cbl-b during Chronic Viral Infection
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“E3 ubiquitin ligases, such as the Casitas B-cell lymphoma (Cbl) family of proteins (c-Cbl, Cbl-b, and Cbl-3), GRAIL, Itch, and Nedd4, are signaling adaptors and have been implicated in induction of T-cell tolerance by regulating the ubiquitination and degradation of downstream effectors of T-cell anergy (3, 5, 21, 30,…”
Background
Molecular basis for checkpoints in the CD8 T cell response: Tolerance versus activation
Mescher, M. F., Agarwal, P., Casey, K. A., Hammerbeck, C. D., Xiao, Z., & Curtsinger, J. (2007) · Seminars in Immunology · doi:10.1016/j.smim.2007.02.007 · Cited by 41
“A role for degradation of components of the T cell signaling pathway in CD4 T cell anergy has also emerged from results showing that a number of E3 ubiquitin ligases have important roles in the induction and maintenance of anergy [71], as discussed elsewhere in this volume.”
Background
The ubiquitin ligase adaptor Ndfip1 regulates T cell-mediated gastrointestinal inflammation and inflammatory bowel disease susceptibility
Ramón, H. E., Riling, C. R., Bradfield, J. P., Yang, B., Hakonarson, H. H., & Oliver, P. M. (2010) · Mucosal Immunology · doi:10.1038/mi.2010.69 · Cited by 38
p85β phosphoinositide 3-kinase regulates CD28 coreceptor function
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Flow Cytometry Contributions for the Diagnosis and Immunopathological Characterization of Primary Immunodeficiency Diseases With Immune Dysregulation
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SOCS-6 Negatively Regulates T Cell Activation through Targeting p56 to Proteasomal Degradation
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Lysosomal ubiquitin and the demise of Mycobacterium tuberculosis
Purdy, G. E., & Russell, D. G. (2007) · Cellular Microbiology · doi:10.1111/j.1462-5822.2007.01039.x · Cited by 35
“The data are compelling; however, given the pleotropic roles of E3 ubiquitin ligases in immune regulation, the suggestion of a direct effect remains speculative (Liu, 2004; Mueller, 2004).”
Background
Mutation in ITCH Gene Can Cause Syndromic Multisystem Autoimmune Disease With Acute Liver Failure
Kleine-Eggebrecht, N., Staufner, C., Kathemann, S., Elgizouli, M., Kopajtich, R., Prokisch, H., & Lainka, E. (2019) · PEDIATRICS · doi:10.1542/peds.2018-1554 · Cited by 34
“Through different signaling pathways, ubiquitination plays an important role in immune regulation and controls T-cell responsiveness.(1,6) In Itch2/2 mice, elevated levels of circulating immunoglobulins, antinuclear antibodies, and lymphocytes could be verified, and several studies revealed that mouse mutations in Itc…”
Background
NFAT-dependent and -independent exhaustion circuits program maternal CD8 T cell hypofunction in pregnancy
Lewis, E. L., Xu, R., Beltra, J., Ngiow, S. F., Cohen, J. B., Telange, R., Crane, A., Sawinski, D. L., Wherry, E. J., & Porrett, P. M. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20201599 · Cited by 32
Mechanisms of T Cell Tolerance and Suppression in Cancer Mediated by Tumor-Associated Antigens and Hormones
Adler, A. J. (2007) · Current Cancer Drug Targets · doi:10.2174/156800907780006931 · Cited by 33
Peripheral tolerance in CD8+ T cells
Srinivasan, M., & Frauwirth, K. A. (2009) · Cytokine · doi:10.1016/j.cyto.2009.01.010 · Cited by 32
Chapter 5 Dysregulation of T Cell Peripheral Tolerance in Type 1 Diabetes
Tisch, R., & Wang, B. (2008) · Advances in immunology · doi:10.1016/s0065-2776(08)00805-5 · Cited by 33

Authors: Mueller, D. L.
Affiliations: University of Minnesota (US)
Corresponding author: Mueller, Daniel L
ORCID: Mueller, Daniel L
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2004-08-27
Volume: 5
Issue: 9
Pages: 883-890
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/ni1106
OpenAlex: W2005935110
Cited by: 224
References: 73
Citations by year: 2026: 2 · 2025: 2 · 2024: 5 · 2023: 7 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 7 · 2018: 7 · 2017: 5 · 2016: 7 · 2015: 5 · 2014: 14 · 2013: 11 · 2012: 7
FWCI: 1.90
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of General Medical Sciences (R01 GM54706, R01GM054706)
National Institute of Allergy and Infectious Diseases (P01AI50162, P01-AI 35296, P01AI050162, P01AI035296)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: E3 ubiquitin ligase, T cell anergy, HECT E3 ligases, RING E3 ligases, ubiquitination, self-tolerance, c-Cbl, Cbl-b, GRAIL, pruritus, NEDD4, T cell proliferation
MeSH terms: Animals, Humans, T-Lymphocytes, Signal Transduction, Self Tolerance, Clonal Anergy, Models, Immunological, Ubiquitin-Protein Ligases

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E3 ubiquitin ligases as T cell anergy factors

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