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| SERGIO D.
CATZ
Molecular and
Experimental Medicine |
Contact
The Scripps Research Institute
Department of Molecular and Experimental
Medicine |
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Scientific Interest The mechanism underlying neutrophil exocytosis Exocytosis in neutrophils is a crucial event in inflammation and innate immune response. Neutrophils contain four types of secretory organelles that hold a variety of specialized proteins which are essential for the microbicidal activity of these cells. The hierarchy that characterizes the secretory process of these granules correlates with the different roles of their cargo proteins in the processes of adhesion, migration, chemotaxis, phagocytosis and the production of reactive oxygen species. Tight regulation of the exocytic process is especially necessary in neutrophils because unrestricted release of the toxic content of their granules is injurious to the host. The small GTPase Rab27a plays a central role in the regulation of exocytosis. Rab27a is the only Rab directly associated with a human genetic disease, Griscelli syndrome (GS). Patients with GS develop an immunodeficiency disorder characterized by malfunction of cytotoxic T-lymphocytes and impaired natural killer cell function. We have recently shown that Rab27a and its counterpart effectors coordinate the exocytic dynamics of neutrophil granules. Our future studies aim to elucidate the differential mechanisms underlying the regulation of granule mobilization to the plasma membrane or to the phagosome using genetic and cellular biology approaches. Our long-term goal is to develop molecular therapeutic strategies to prevent uncontrolled release of neutrophil granule cargo proteins. Understanding Toll-like receptor signaling to improve the innate immune response to polymicrobial infections Increasing evidence indicates the importance of mixed bacterial infections in the modulation of the pathogenicity of the individual bacterial strains, the concomitant host response, and the course and outcome of infectious diseases. Evidence suggests that during mixed infections the pathophysiology of one microorganism is affected by the co-infecting bacteria. Little is known about how the microorganisms modulate the host immune response during mixed infections. Our research is directed at understanding the molecular mechanisms that regulate the neutrophil response during mixed infections. In particular, we attempt to elucidate the TLR-signaling involved in this regulation, and dissect the signaling mechanisms that mediate synergism or tolerance during mixed infections. Other scientific Interests
Past and Present Lab Members
Selected Publications (for complete list of publications please refer to www.pubmed.gov) Agnieszka A. Brzezinska, Jennifer L. Johnson, Daniela B. Munafo, Karine Crozat, Bruce Beutler, William B. Kiosses, Beverly A. Ellis and Sergio D. Catz. (2008) The Rab27a effectors JFC1/Slp1 and Munc13-4 regulate exocytosis of neutrophil granules. Traffic DOI: 10.1111/j.1600-0854.2008.00838.x Agnieszka A. Brzezinska, Jennifer L. Johnson, Daniela B. Munafo, Beverly A. Ellis and Sergio D. Catz. (2008) Signaling mechanisms for Toll-like receptor-activated neutrophil exocytosis: key roles for IRAK-4 and PI3-kinase but not TRIF. Immunology, in press Catz S.D. (2008) Characterization of Rab27a and JFC1 as constituents of the secretory machinery of prostate-specific antigen in prostate carcinoma cells. Methods in Enzymology, vol 438: 25-40 Pacquelet S, Johnson JL, Ellis BA, Brzezinska AA, Lane WS, Munafo DB and Catz S.D. (2007) Cross-talk between IRAK-4 and the NADPH oxidase. Biochemical Journal. 403(3):451-61. Munafo DB, Johnson JL, Ellis BA, Rutschmann S, Beutler B and Catz S.D. (2007) Rab27a is a key component of the secretory machinery of azurophilic granules in granulocytes. Biochemical Journal. 402(2):229-39 J.L. Johnson, B.A. Ellis, D. Noack, M.C. Seabra and Catz, S.D. (2005). The Rab27a-binding protein, JFC1, regulates androgen-dependent secretion of prostate-specific antigen and prostatic-specific acid phosphatase. Biochemical Journal. 391: 699-710. J. L. Johnson, S. Pacquelet, W.S. Lane, B. Eam and Catz, S.D. (2005) Akt Regulates the Subcellular Localization of the Rab27a-Binding Protein JFC1 by Phosphorylation. Traffic 6(8):667-81. Catz, S.D., Johnson, J.L. & Babior, B.M. (2002) The C2A domain of JFC1 binds to 3-phosphorylated phosphoinositides and directs plasma membrane association in living cells. Proc.Natl.Acad.Sci.U.S.A. 99(18):11652-11657. Catz, S.D., Babior, B.M. & Johnson, J.L. (2002) JFC1 is transcriptionally activated by nuclear factor kB and up-regulated by tumor necrosis factor a in prostate carcinoma cells. Biochemical Journal, 367:791-9. Catz, S.D. & Johnson, J.L. (2001) Transcriptional regulation of bcl-2 by nuclear factor kappaB and its significance in prostate cancer. Oncogene, 20, 7342-735. |
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