Phagosomal targeting of CARD proteins Phagocytosis is the process by which cells such as macrophages and dendritic cells bind, internalize, and kill microbes. Several different types of receptors are known to recognize microbes (either directly or through opsonization) and to trigger phagocytosis. The cell biological mechanisms by which these receptors drive phagocytosis are dependent the specific receptor. Thus, Fc-receptor mediated phagocytosis recruits a distinct set of cytoskeletal components than Dectin-1 (beta-glucan receptor) or complement receptor-mediated phagocytosis. Phagocytosis is tightly coupled to the initiation of inflammatory cytokine and chemokine production, although the mechanisms by which these processes are coupled are still being elucidated. Caspase Activation and Recruitment Domains (CARDs) are conserved protein-protein interaction domains found in a variety of cytoplasmic proteins key to microbial recognition and inflammatory signaling including Nod (nuclear oligomerization domain) proteins, Bcl10, Nalp1 and many others. We have observed that several CARD proteins are recruited to phagosomes. We hypothesize that CARD recruitment to phagosomes is a key mechanism by which signals for phagocytosis and inflammation are integrated. In this study, we will define the mechanism(s) by which CARD proteins are recruited to phagosomes and whether CARD proteins are recruited only to specific types of phagosomes (Aim1). We will determine what protein-protein interactions are required to get CARD proteins to phagosomes and whether these interactions are important for inflammatory signaling (Aim 2). We will determine whether activating a CARD protein (Nod2) on phagosomes alters its inflammatory signaling consequences, and whether such targeted activation influences antigen presentation and the type of adaptive immune response that is promoted.
White blood cells eat and kill infectious microbes. They also initiate inflammatory responses that are crucial for defense against infection. We are defining how the molecular signaling pathways that control the processes of eating and killing microbes are connected to the signaling pathways required to activate inflammation. Clinical manipulation of these pathways may help suppress unwanted inflammation, or stimulate effective immune defenses.
|Kaplan, Amber; Lee, Michelle W; Wolf, Andrea J et al. (2017) Direct Antimicrobial Activity of IFN-?. J Immunol 198:4036-4045|
|Wolf, Andrea J; Liu, George Y; Underhill, David M (2017) Inflammatory properties of antibiotic-treated bacteria. J Leukoc Biol 101:127-134|
|Wolf, Andrea J; Reyes, Christopher N; Liang, Wenbin et al. (2016) Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan. Cell 166:624-636|
|O'Rourke, J G; Bogdanik, L; Yáñez, A et al. (2016) C9orf72 is required for proper macrophage and microglial function in mice. Science 351:1324-9|
|Müller, Sabrina; Wolf, Andrea J; Iliev, Iliyan D et al. (2015) Poorly Cross-Linked Peptidoglycan in MRSA Due to mecA Induction Activates the Inflammasome and Exacerbates Immunopathology. Cell Host Microbe 18:604-12|
|Parsons, Matthew W; Li, Li; Wallace, Aaron M et al. (2014) Dectin-2 regulates the effector phase of house dust mite-elicited pulmonary inflammation independently from its role in sensitization. J Immunol 192:1361-71|
|Ma, Jun; Becker, Courtney; Reyes, Christopher et al. (2014) Cutting edge: FYCO1 recruitment to dectin-1 phagosomes is accelerated by light chain 3 protein and regulates phagosome maturation and reactive oxygen production. J Immunol 192:1356-60|
|Underhill, David M; Goodridge, Helen S (2012) Information processing during phagocytosis. Nat Rev Immunol 12:492-502|
|Shimada, Kenichi; Crother, Timothy R; Karlin, Justin et al. (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36:401-14|
|Kaplan, Amber; Ma, Jun; Kyme, Pierre et al. (2012) Failure to induce IFN-ýý production during Staphylococcus aureus infection contributes to pathogenicity. J Immunol 189:4537-45|
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