Asthma is a chronic inflammatory disease that affects nearly 300 million people worldwide, patients suffered allergic asthma manifest various recurring symptoms, including reversible airflow obstruction, bronchial hyperresponsiveness(BHR) and airway inflammation.
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. For instance, Itch, a member of Nedd4 family, was reported to regulate Th2 differentiation through targeting the transcription factor JunB for ubiquitin-mediated degradation. Compared with E3 ubiquitin ligases, the roles of deubiquitinase(DUBs) in the regulation of TCR signaling and function are poorly characterized.
In a study reported online September 17, 2018, in Journal of Experimental Medicine, scientists firstly identified ubiquitin-specific peptidase 38 (USP38), a member of DUBs family, is essential for Th2-mediated asthma. The study 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.
Moreover, USP38 has been shown to be 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), further suggesting that CD4+ T cell-derived USP38 participate in Th2 differentiation. Mechanistically, the researchers also demonstrated that USP38 can directly associated with JunB to remove its Lys-48–linked poly-ubiquitination to block JunB degradation.
USP38 stabilizes JunB in TCR signaling(Image by Prof QIAN Youcun's Group)
This study 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, the researchers found that Itch protein level was not regulated by TCR activation. While USP38 was induced with the kinetics similar to that of JunB, the study suggested 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 research by Porf. Qian Youcun's Group from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences was entitled “USP38 critically promotes asthmatic pathogenesis by stabilizing JunB protein”, and was mainly supported by the National Natural Science Foundation of China, National Key Research and Development Program of China and Chinese Academy of Sciences.
WANG Jin (Ms.)
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences