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

Hyun Jung Koh, Ye Ram Kim, Jae Sung Kim, Jin Seung Yun, Sojin Kim, Sun Young Kim, Kiseok Jang, Chul Su Yang

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number62
JournalExperimental and Molecular Medicine
Volume50
Issue number5
DOIs
StatePublished - 2018 May 1

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Macrophages
Mycobacterium tuberculosis
Tuberculosis
Phagosomes
Core Binding Factor Alpha 2 Subunit
Tumors
Genes
Cytokines
Membranes
Survival
Mycobacterium
Granuloma
Tumor Suppressor Genes
Innate Immunity
Virulence
Growth

Cite this

Koh, Hyun Jung ; Kim, Ye Ram ; Kim, Jae Sung ; Yun, Jin Seung ; Kim, Sojin ; Kim, Sun Young ; Jang, Kiseok ; Yang, Chul Su. / CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22. In: Experimental and Molecular Medicine. 2018 ; Vol. 50, No. 5.
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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.",
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CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22. / Koh, Hyun Jung; Kim, Ye Ram; Kim, Jae Sung; Yun, Jin Seung; Kim, Sojin; Kim, Sun Young; Jang, Kiseok; Yang, Chul Su.

In: Experimental and Molecular Medicine, Vol. 50, No. 5, 62, 01.05.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22

AU - Koh, Hyun Jung

AU - Kim, Ye Ram

AU - Kim, Jae Sung

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AU - Kim, Sojin

AU - Kim, Sun Young

AU - Jang, Kiseok

AU - Yang, Chul Su

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AB - 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.

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