E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination

Yixia Zhao; Hui Guo; Guilin Qiao; Mark Zucker; Wallace Y Langdon; Jian Zhang

doi:10.4049/jimmunol.1402434

Back

E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination

Journal article

Peer reviewed

E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination

Yixia Zhao, Hui Guo, Guilin Qiao, Mark Zucker, Wallace Y Langdon and Jian Zhang

The Journal of immunology (1950), Vol.194(4), pp.1639-1645

02/15/2015

DOI: 10.4049/jimmunol.1402434

PMCID: PMC4324371

PMID: 25560411

View Online

Abstract

CD28 costimulation is essential for the development of thymic-derived CD4(+)CD25(+)Foxp3(+) regulatory T cells ("tTregs"). E3 ubiquitin ligase Cbl-b has been shown to regulate CD28 dependence of T cell activation. In this paper, we report that the loss of Cbl-b partially but significantly rescues the defective development of tTregs in Cd28(-/-) mice. This partial rescue is independent of IL-2. Mechanistically, Cbl-b binds to Foxp3 upon TCR stimulation and, together with Stub1, targets Foxp3 for ubiquitination and subsequently degradation in the proteasome. As Cbl-b self-ubiquitination and proteasomal degradation is impaired in Cd28(-/-) T cells, the defective development of tTregs in Cd28(-/-) mice may in part be due to increased Foxp3 ubiquitination and degradation targeted by Stub1 and Cbl-b. Treating Cd28(-/-) mice with a proteasome inhibitor completely rescues defective tTreg development in these mice. Therefore, Cbl-b, together with Stub1, ubiquitinate Foxp3, and regulate tTreg development.

Forkhead Transcription Factors - immunology

Mice, Inbred C57BL

Thymus Gland - cytology

Ubiquitin-Protein Ligases - metabolism

Mice, Knockout

T-Lymphocytes, Regulatory - immunology

Lymphocyte Activation - immunology

Ubiquitin-Protein Ligases - immunology

Ubiquitination

Animals

Transfection

Forkhead Transcription Factors - metabolism

Adaptor Proteins, Signal Transducing - immunology

Thymus Gland - immunology

Mice

Mice, Inbred BALB C

Proto-Oncogene Proteins c-cbl - immunology

Details

Title: Subtitle: E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination
Creators: Yixia Zhao - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210
Hui Guo - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210
Guilin Qiao - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637; and
Mark Zucker - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210
Wallace Y Langdon - School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia
Jian Zhang - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210; Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637; and jian.zhang@osumc.edu
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.194(4), pp.1639-1645
DOI: 10.4049/jimmunol.1402434
PMID: 25560411
PMCID: PMC4324371
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: United States
Grant note: R01 AI090901 / NIAID NIH HHS
Language: English
Date published: 02/15/2015
Academic Unit: Pathology
Record Identifier: 9984047656902771

Metrics

17 Record Views

38 Times Cited - Web of Science

See more details