title: Toxoplasma gondii GRA7-Targeted ASC and PLD1 Promote Antibacterial Host Defense via PKCα.
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.
authors.affiliation: Department of Molecular and Life Science, College of Science and Technology, Hanyang University, Ansan, S. Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Koh
authors.affiliation: Department of Molecular and Life Science, College of Science and Technology, Hanyang University, Ansan, S. Korea.
authors.forename: Ye-Ram
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Department of Molecular and Life Science, College of Science and Technology, Hanyang University, Ansan, S. Korea.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Molecular and Life Science, College of Science and Technology, Hanyang University, Ansan, S. Korea.
authors.forename: Jin-Seung
authors.initials: JS
authors.lastname: Yun
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul, S. Korea.
authors.forename: Kiseok
authors.identifier: 0000-0002-6585-3990
authors.initials: K
authors.lastname: Jang
authors.affiliation: Department of Molecular and Life Science, College of Science and Technology, Hanyang University, Ansan, S. Korea.
authors.forename: Chul-Su
authors.identifier: 0000-0003-4918-961X
authors.initials: CS
authors.lastname: Yang
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000378:metabolism*; D000071476:Caspase Activation and Recruitment Domain; D002454:Cell Differentiation; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009161:Mycobacterium / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D000071196:Pyrin Domain; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D014122:Toxoplasma / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology
chemical_list: D000953:Antigens, Protozoan; C112573:GRA7 protein, Toxoplasma gondii; D058847:Inflammasomes; D015800:Protozoan Proteins; D048029:TNF Receptor-Associated Factor 6; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha