Abstract
The tumor suppressor gene CD82/KAI1 is a member of the tetraspanin superfamily and organizes various membrane-based processes. Mycobacterium tuberculosis (MTB) persists in host macrophages by interfering with phagolysosome biogenesis and inflammatory responses, but the role of CD82 in controlling the intracellular survival of pathogenic mycobacteria within macrophages remains poorly understood. In this study, we demonstrated that the virulent MTB strain H37Rv (MTB Rv) induced CD82 promoter hypomethylation, resulting in CD82 expression. Targeting of the runt-related transcription factor 1 (RUNX1) by CD82 is essential for phagosome arrest via interacting with Rab5/22. This arrest is required for the intracellular growth of MTB in vitro and in vivo, but not for that of MTB H37Ra (MTB Ra) in macrophages. In addition, knockdown or knockout of CD82 or RUNX1 increased antibacterial host defense via phagolysosome biogenesis, inflammatory cytokine production, and subsequent antimicrobial activity both in vitro and in vivo. Notably, the levels of CD82 and RUNX1 in granulomas were elevated in tuberculosis (TB) patients, indicating that CD82 and RUNX1 have clinical significance in human TB. Our findings identify a previously unrecognized role of CD82 hypomethylation in the regulation of phagosome maturation, enhanced intracellular survival, and the innate host immune response to MTB. Thus, the CD82–RUNX1–Rab5/22 axis may be a previously unrecognized virulence mechanism of MTB pathogenesis.
Highlights
CD82/KAI1, a member of the tetraspanin family, is a cancer metastasis suppressor that has been implicated in diverse biological processes, including fusion, adhesion, migration, apoptosis, and cell morphology alteration[1,2]
CD82 contributes to TB pathogenesis To identify the Mycobacterium tuberculosis (MTB) virulence mechanisms involved in controlling intracellular survival of pathogenic mycobacteria in MTB-infected macrophages, we conducted differential gene expression profiling of murine lungs exposed to MTB strain H37Rv (MTB Rv) or MTB H37Ra (MTB Ra) using RNA-seq analysis
RNAseq and quantitative real-time PCR analyses showed that CD82/KAI1 were the most significantly upregulated genes expressed in MTB Rv versus MTB Ra infection (Fig. 1a, b and S1B)
Summary
CD82/KAI1, a member of the tetraspanin family, is a cancer metastasis suppressor that has been implicated in diverse biological processes, including fusion, adhesion, migration, apoptosis, and cell morphology alteration[1,2]. The downregulation of CD82 expression is associated with advanced stages of several human cancers and correlates with the acquisition of metastatic potential[1,2,3]. Official journal of the Korean Society for Biochemistry and Molecular Biology. The regulation of CD82 gene expression is becoming an increasingly important issue. The transcriptional silencing of genes is caused by epigenetic mechanisms, including DNA methylation and histone modification, as well as by regulation via non-coding RNAs, which play pivotal roles in disease development[7,8,9]. Neither the involvement of such an epigenetic regulation of CD82 expression in tuberculosis (TB) pathogenesis nor the mechanisms by which CD82 is involved in controlling the intracellular survival of pathogenic mycobacteria in macrophages are well understood
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