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Scientists Identify a New Deubiquitinase Specifically for Th2 Immunity and Associated Asthma

Sep 19, 2018

Asthma is a chronic inflammatory disease that affects nearly 300 million people worldwide. Patients suffered allergic asthma manifest various recurring symptoms.

It was well established that type 2 T-helper (Th2) cells play critical roles in the pathogenesis of allergic asthma by producing characteristic cytokines IL-4, IL-5 and IL-13. Th2 differentiation is dependent on the recognition of cognate antigens by T-cell receptor (TCR) which triggers signals to activate downstream transcription factors. 

Ubiquitination is an important protein modification to regulate TCR signal transduction and T-helper cell subsets differentiation. Compared with E3 ubiquitin ligases, the roles of deubiquitinase (DUBs) in the regulation of TCR signaling and function are poorly characterized. 

In a recent study published in Journal of Experimental Medicine, Porf. QIAN Youcun's Group at Shanghai Institute of Nutrition and Health of Chinese Academy of Sciences firstly identified that ubiquitin-specific peptidase 38 (USP38), a member of DUBs family, is essential for Th2-mediated asthma, and demonstrated that TCR stimulation up-regulated the USP38 level and the increased USP38 in turn mediated stabilization of the JunB protein, a transcription factor critical for the Th2 development. 

Researchers revealed that USP38 is required for the Th2 cytokines production induced by TCR stimulation and Th2 development both in vitro and in vivo. With one accord, USP38 deficiency mice (usp38-/-) as well as mice selectively deletion with USP38 in T cells(usp38f/fCd4-Cre) were resistant to allergic asthma induction by ovalbumin (OVA) or house-dust mite (HDM), suggesting that CD4+ T cell-derived USP38 participate in Th2 differentiation. 

Mechanistically, they demonstrated that USP38 can directly associated with JunB to remove its Lys-48–linked poly-ubiquitination to block JunB degradation, and identified USP38 as the first DUB to regulate Th2 response. It was reported that JunB, a critical transcription factor in Th2 differentiation, can be targeted by E3 ligase Itch for degradation. 

In addition, the protein lever of JunB along with the E3 ligase activity of Itch can be promoted by TCR signaling. However, researchers found that Itch protein level was not regulated by TCR activation while USP38 was induced with the kinetics similar to that of JunB, suggesting that USP38 induction may function as a signal to break the checkpoint for boosting Th2 response. 

A USP38-containing genomic locus has been reported to be associated with the adult asthma in a genome-wide association study (GWAS). The pathophysiological role of USP38 in Th2 immunity makes it an attractive pharmacological target for treating Th2-mediated inflammatory diseases such as asthma. In future, small inhibitors against USP38 may be developed to block its enzyme activity. 

This study was mainly supported by the National Natural Science Foundation of China, National Key Research and Development Program of China and Chinese Academy of Sciences. 

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