Regulation of IL-4 receptor signaling by STUB1 in lung inflammation

TitleRegulation of IL-4 receptor signaling by STUB1 in lung inflammation
Publication TypeJournal Article
Year of Publication2014
AuthorsWei Q, Sha Y, Bhattacharya A, Fattah EAbdel, Bonilla D, Jyothula SSSK, Pandit L, Hershey GKKhurana, N Eissa T
JournalAm J Respir Crit Care Med
Volume189
Issue1
Pagination16-29
Date Published2014 Jan 1
ISSN1535-4970
KeywordsAdult, Animals, Asthma, Child, Down-Regulation, Female, Flow Cytometry, Humans, Immunoblotting, Immunoprecipitation, Macrophage Activation, Male, Mice, Mice, Knockout, Pneumonia, Proteasome Endopeptidase Complex, Pulmonary Disease, Chronic Obstructive, Real-Time Polymerase Chain Reaction, Receptors, Cell Surface, Receptors, Interleukin-4, Signal Transduction, STAT6 Transcription Factor, Ubiquitin, Ubiquitin-Protein Ligases
Abstract

RATIONALE: IL-4Rα, the common receptor component for IL-4 and IL-13, plays a critical role in IL-4- and IL-13-mediated signaling pathways that regulate airway inflammation and remodeling. However, the regulatory mechanisms underlying IL-4Rα turnover and its signal termination remain elusive.

OBJECTIVES: To evaluate the role of STUB1 (STIP1 homology and U-Box containing protein 1) in regulating IL-4R signaling in airway inflammation.

METHODS: The roles of STUB1 in IL-4Rα degradation and its signaling were investigated by immunoblot, immunoprecipitation, and flow cytometry. The involvement of STUB1 in airway inflammation was determined in vivo by measuring lung inflammatory cells infiltration, mucus production, serum lgE levels, and alveolar macrophage M2 activation in STUB1(-/-) mice. STUB1 expression was evaluated in airway epithelium of patients with asthma and lung tissues of subjects with chronic obstructive pulmonary disease.

MEASUREMENTS AND MAIN RESULTS: STUB1 interacted with IL-4Rα and targeted it for ubiquitination-mediated proteasomal degradation, terminating IL-4 or IL-13 signaling. STUB1 knockout cells showed increased levels of IL-4Rα and sustained STAT6 activation, whereas STUB1 overexpression reduced IL-4Rα levels. Mice deficient in STUB1 had spontaneous airway inflammation, alternative M2 activation of alveolar macrophage, and increased serum IgE. STUB1 levels were increased in airways of subjects with asthma or chronic obstructive pulmonary disease, suggesting that up-regulation of STUB1 might be an important feedback mechanism to dampen IL-4R signaling in airway inflammation.

CONCLUSIONS: Our study identified a previously uncharacterized role for STUB1 in regulating IL-4R signaling, which might provide a new strategy for attenuating airway inflammation.

DOI10.1164/rccm.201305-0874OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID24251647
PubMed Central IDPMC3919125
Grant ListP30AI036211 / AI / NIAID NIH HHS / United States
P30CA125123 / CA / NCI NIH HHS / United States
S10RR024574 / RR / NCRR NIH HHS / United States
T32-5T32AI007456 / AI / NIAID NIH HHS / United States