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| SERGIO D. CATZ
Molecular and
Experimental Medicine |
Contact
The Scripps Research
Institute |
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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. Vesicular trafficking in lysosomal storage disease (LSD) LSD are genetic or
acquired diseases characterized by anomalous accumulation of
metabolites in the lysosomes. Increased levels of intralysosomal
metabolites leads to cell malfunction and cell death. We have special
interest in developing strategies directed at upregulating the
vesicular trafficking pathways of cells that have accumulated
metabolites in their lysosomes to restore normal cellular function and
prevent cell death. We are currently exploring several trafficking
pathways and utilizing high-throughput screening approaches to identify
potential novel therapies for the treatment of LSDs. 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. Other scientific Interests
Past and Present Lab Members
Selected Publications (for complete list of publications please refer to www.pubmed.gov) Johnson JL, Hong H,
Monfregola J, Catz SD.
Increased survival and reduced neutrophil infiltration of the
liver in Rab27a- but not Munc13-4-deficient mice in LPS-induced
systemic inflammation. Infection
& Immunity, 2011; PMID: 21746860 Johnson JL, Hong H,
Monfregola J, Kiosses WB, and Catz SD.
MUNC13-4 restricts motility of RAB27A-expressing vesicles to facilitate
lipopolysaccharide-induced priming of exocytosis in neutrophils. J. Biol. Chem., 2011 286(7):5647-56 Agnieszka A.
Brzezinska, Jennifer L. Johnson, Daniela B. Munafo, Beverly A. Ellis
and Catz.S.D Signaling
mechanisms for Toll-like receptor-activated neutrophil exocytosis: key
roles for IRAK-4 and PI3-kinase but not TRIF. Immunology, 2009;
127(3):386-97 Agnieszka A. Brzezinska, Jennifer L. Johnson, Daniela B. Munafo, Karine Crozat, Bruce Beutler, William B. Kiosses, Beverly A. Ellis and Catz S.D The Rab27a effectors JFC1/Slp1 and Munc13-4 regulate exocytosis of neutrophil granules. Traffic, 2008; 9: 2151–2164 Catz S.D. Characterization of Rab27a and JFC1 as constituents of the secretory machinery of prostate-specific antigen in prostate carcinoma cells. Methods in Enzymology, 2008; 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. Munafó 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 kappaB and up-regulated by tumor necrosis factor alpha 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, 7342-7351. . |
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