Research
In recent years, researchers have gradually realized that targeting host key factors improving host immunity, which is named host-directed therapy (HDT), is an effective strategy to eliminate pathogens including drug-resistant pathogens. However, the host factors and their regulatory mechanisms involved in host immune defense against Mycobacterium tuberculosis (Mtb) are largely unexplored, which impedes the application of HDT in Tuberculosis (TB) treatment. Prof. WANG Jing and Prof. LIU Cui Hua’s lab at Institute of Microbiology of Chinese Academy of Sciences revealed the key host factor regulating autophagy flux during Mtb infection and the underlying mechanism, which can provide precise targets and strategies for the development of autophagy-based HDT to prevent and control TB. This work was published in Autophagy.
The tripartite motif (TRIM) family proteins are a class of ubiquitin ligases widely involved in cell biological processes. By analyzing the gene expression of TRIM proteins in peripheral blood, researchers found that TRIM27 gene transcription in TB patients was significantly lower than that of healthy individuals. Further Mtb infection experiments showed the level of nuclear TRIM27 increased upon Mtb infection and then the nuclear TRIM27 functioned as a transcription activator to promote the transcription of TFEB (transcription factor EB), a critical regulator promoting autophagy-related gene expression. Specifically, TRIM27 not only binds to the promoter region of TFEB through its DNA-binding motif, but also interacts with the TFEB transcription factor CREB1 (cAMP responsive element binding protein 1) through its RFP domain, thus increasing the affinity of CREB1 to the TFEB promoter and promoting CREB1 transcription activity towards TFEB, eventually enhancing TFEB gene transcription and the ensuing autophagy-related gene expression and autophagy activation to clear Mtb. Furthermore, TFEB activator 1 can rescue the attenuated autophagy flux and reduced Mtb clearance in Trim27-deficient cell and mouse models (Figure).
This study identifies that TRIM27 is a critical host factor promoting autophagy flux during Mtb infection, suggesting that TRIM27 is a potential biomarker that may serve as an indicator of TB status. In addition, for individuals with TRIM27 deficiency, enhancing TFEB transcription and activity is the potential effective HDT for TB prevention and treatment.
This work was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China.
Figure: Proposed model depicting host E3 ubiquitin ligaseTRIM27 elicits protective immunity against TB by activating TFEB-mediated autophagy flux (Image by Prof. WANG Jing and Prof. LIU Cui Hua’s group)
Contact: WANG Jing Institute of Microbiology, Chinese Academy of Sciences Phone: 86-010-64806189 E-mail: wangj6@im.ac.cn