E3 Ubiquitin Ligase Cbl-b Suppresses Proallergic T Cell Development and Allergic Airway Inflammation

Guilin Qiao; Haiyan Ying; Yixia Zhao; Yanran Liang; Hui Guo; Huifeng Shen; Zhenping Li; Julian Solway; Enxiang Tao; Y. Jeffrey Chiang; Stanley Lipkowitz; Josef M Penninger; Wallace Y Langdon; Jian Zhang

doi:10.1016/j.celrep.2014.01.012

Back

E3 Ubiquitin Ligase Cbl-b Suppresses Proallergic T Cell Development and Allergic Airway Inflammation

Journal article

Open access

Peer reviewed

E3 Ubiquitin Ligase Cbl-b Suppresses Proallergic T Cell Development and Allergic Airway Inflammation

Guilin Qiao, Haiyan Ying, Yixia Zhao, Yanran Liang, Hui Guo, Huifeng Shen, Zhenping Li, Julian Solway, Enxiang Tao, Y. Jeffrey Chiang, …

Cell reports (Cambridge), Vol.6(4), pp.709-723

02/27/2014

DOI: 10.1016/j.celrep.2014.01.012

PMCID: PMC3969736

PMID: 24508458

Files and links (1)

url

https://doi.org/10.1016/j.celrep.2014.01.012View

Published (Version of record) Open Access

Abstract

E3 ubiquitin ligase Cbl-b has emerged as a gatekeeper that controls the activation threshold of the T cell antigen receptor and maintains the balance between tolerance and autoimmunity. Here, we report that the loss of Cbl-b facilitates T helper 2 (Th2) and Th9 cell differentiation in vitro. In a mouse model of asthma, the absence of Cbl-b results in severe airway inflammation and stronger Th2 and Th9 responses. Mechanistically, Cbl-b selectively associates with Stat6 upon IL-4 ligation and targets Stat6 for ubiquitination and degradation. These processes are heightened in the presence of T cell receptor (TCR)/CD28 costimulation. Furthermore, we identify K108 and K398 as Stat6 ubiquitination sites. Intriguingly, introducing Stat6 deficiency into Cblb−/− mice abrogates hyper-Th2 responses but only partially attenuates Th9 responses. Therefore, our data reveal a function for Cbl-b in the regulation of Th2 and Th9 cell differentiation. [Display omitted] •Loss of Cbl-b results in heightened Th2/Th9 responses and severe airway inflammation•Cbl-b is the E3 ubiquitin ligase for Stat6•Stat6 deficiency abrogates hyper-Th2 responses but partially impairs Th9 responses•Cbl-b regulates Th9 in both Stat6-dependent and -independent mechanisms The proallergic T cell subsets Th2 and Th9 cells are the major mediators of allergic airway inflammation. Here, Qiao, Zhang, and colleagues show that the E3 ubiquitin ligase Cbl-b suppresses allergic airway inflammation by targeting Stat6 for ubiquitination and proteasomal degradation, which leads to the inhibition of both Th2 and Th9 responses. They also find that inhibition of Th9 responses by Cbl-b involves both Stat6-dependent and -independent mechanisms. Therefore, Cbl-b is a potential drug target for treating allergic asthma.

Details

Title: Subtitle: E3 Ubiquitin Ligase Cbl-b Suppresses Proallergic T Cell Development and Allergic Airway Inflammation
Creators: Guilin Qiao - Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
Haiyan Ying - Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
Yixia Zhao - Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
Yanran Liang - Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
Hui Guo - Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
Huifeng Shen - Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH 43210, USA
Zhenping Li - Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
Julian Solway - Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
Enxiang Tao - Department of Neurology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China
Y. Jeffrey Chiang - Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Stanley Lipkowitz - Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Josef M Penninger - Institute of Molecular Biotechnology, Austrian Academy of Sciences, 1030 Vienna, Austria
Wallace Y Langdon - School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA 6009, Australia
Jian Zhang - Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.6(4), pp.709-723
Publisher: Elsevier Inc
DOI: 10.1016/j.celrep.2014.01.012
PMID: 24508458
PMCID: PMC3969736
ISSN: 2211-1247
eISSN: 2211-1247
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: AI090901, R01 AR04775; DOI: 10.13039/100000968, name: American Heart Association, award: 09GRNT2010084
Language: English
Date published: 02/27/2014
Academic Unit: Pathology
Record Identifier: 9984047638102771

Metrics

15 Record Views

51 Times Cited - Web of Science

See more details