Abstract
Tuberculosis is a global health problem and at least one-third of the world's population is infected with Mycobacterium tuberculosis (MTB). MTB is a successful pathogen that enhances its own intracellular survival by inhibiting inflammation and arresting phago-lysosomal fusion. We previously demonstrated that Toxoplasma gondii (T. gondii) dense granule antigen (GRA) 7 interacts with TNF receptor-associated factor 6 via Myeloid differentiation primary response gene 88, enabling innate immune responses in macrophages. To extend these studies, we found that GRA7 interacts with host proteins involved in antimicrobial host defense mechanisms as a therapeutic strategy for tuberculosis. Here, we show that protein kinase C (PKC)α-mediated phosphorylation of T. gondii GRA7-I (Ser52) regulates the interaction of GRA7 with PYD domain of apoptosis-associated speck-like protein containing a carboxy-terminal CARD, which is capable of oligomerization and inflammasome activation can lead to antimicrobial defense against MTB. Furthermore, GRA7-III interacted with the PX domain of phospholipase D1, facilitating its enzyme activity, phago-lysosomal maturation, and subsequent antimicrobial activity in a GRA7-III (Ser135) phosphorylation-dependent manner via PKCα. Taken together, these results underscore a previously unrecognized role of GRA7 in modulating antimicrobial host defense mechanism during mycobacterial infection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Protozoan / genetics
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Antigens, Protozoan / metabolism*
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Caspase Activation and Recruitment Domain
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Cell Differentiation
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Humans
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Immunity, Innate
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Inflammasomes / immunology
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Macrophages / immunology
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Mice
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Mice, Inbred C57BL
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Mycobacterium / immunology*
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Myeloid Cells / immunology
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Phosphorylation
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Protein Kinase C-alpha / genetics
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Protein Kinase C-alpha / metabolism*
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Protozoan Proteins / genetics
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Protozoan Proteins / metabolism*
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Pyrin Domain
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / metabolism
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Toxoplasma / genetics
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Toxoplasma / immunology
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Toxoplasma / physiology*
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Tuberculosis / immunology*
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Tuberculosis / microbiology
Substances
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Antigens, Protozoan
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GRA7 protein, Toxoplasma gondii
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Inflammasomes
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Protozoan Proteins
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TNF Receptor-Associated Factor 6
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PRKCA protein, human
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Protein Kinase C-alpha
Grants and funding
This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIP) the Ministry of Science, ICT & Future Planning (NRF-2014R1A1A1006117 and No. 2011-0030049), by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI16C1653). The funders had role in study design, data collection and analysis, decision to publish, or preparation of the manuscript in Life Science field.