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CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22

Title
CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22
Author
양철수
Keywords
MYCOBACTERIUM-TUBERCULOSIS; METASTASIS SUPPRESSOR; MEMBRANE-PROTEINS; HUMAN MACROPHAGES; CARBON-MONOXIDE; IFN-GAMMA; CELLS; INFECTION; CHROMATIN; CD82/KAI1
Issue Date
2018-05
Publisher
NATURE PUBLISHING GROUP
Citation
EXPERIMENTAL AND MOLECULAR MEDICINE, v. 50, Article no. 62
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.
URI
https://www.nature.com/articles/s12276-018-0091-4https://repository.hanyang.ac.kr/handle/20.500.11754/118657
ISSN
1226-3613; 2092-6413
DOI
10.1038/s12276-018-0091-4
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > BIONANOTECHNOLOGY(바이오나노학과) > Articles
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