ENVIRONMENTAL HEALTH SCIENCES RESEARCH CENTER

A National Institute of Environmental Health Sciences Center of Excellence

 

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William M. Nauseef, M.D.

Professor of Internal Medicine - Infectious Disease

Email: william-nauseef@uiowa.edu
Phone: (319) 356-1739
Lab Web Site: http://www.int-med.uiowa.edu/research/Inflammation/Inflammation.html
EHSRC Role(s): Member, Inflammation and Innate Immunity Research Cluster

Ongoing projects in Dr. Nauseef's laboratory address several questions pertinent to the cell biology of neutrophil-mediated responses during inflammation and host response to infection. We have a longstanding interest in two important aspects of neutrophil biology, namely the NADPH-dependent oxidase and the granule hemeprotein myeloperoxidase (MPO), and are examining various aspects of each during acute inflammation. NADPH-dependent oxidase studies address two major questions. First, how does lipopolysaccharide, a component of most gram-negative bacteria, induce the neutrophil to become "primed" for subsequent activation? Detailed analysis of the subcellular localization and phosphorylation state of p47phox and p67phox are under study. Second, we are examining the role of the membrane-associated cytoskeleton in regulating and/or directing assembly of the NADPH-dependent oxidase. Current attention is focused on p57, a 57-kDa homologue of the protein coronin found in Dictyostelium, and its association with oxidase components and its recruitment to the nascent phagosome.

Studies related to MPO include characterization of MPO biosynthesis and the identification of various genotypes of hereditary MPO deficiency. These include include characterization of the role of molecular chaperones calreticulin and calnexin as well as assessment of the various "quality control" mechanisms operating in the endoplasmic reticulum. We are searching for peptide motifs recognized by calreticulin and calnexin in their roles as chaperones. Studies are ongoing to define the mechanism by which heme is incorporated into MPO and the impact of heme insertion on the subsequent proteolytic processing and intracellular targeting of MPO. Studies of hereditary MPO deficiency include identification of the specific genotype and then characterization of the impact of that mutation on synthesis of MPO. For these studies we use transfected K562 cells to express mutant MPO cDNA and characterize the biosynthesis. Our findings from such analysis complement well those derived from studies of MPO biosynthesis in established myeloid cell lines.

Recent Publications

  1. Nakano Y, Banfi B, Jesaitis AJ, Dinauer MC, Allen LA, Nauseef WM. Critical roles for p22phox in the structural maturation and subcellular targeting of Nox3. Biochem J. 2007 Apr 1;403(1):97-108.
  2. 2: Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB Jr, Nauseef WM, Dupuy C, Banfi B. A novel host defense system of airways is defective in cystic fibrosis. Am J Respir Crit Care Med. 2007 Jan 15;175(2):174-83. Epub 2006 Nov 2.
  3. 3: Simons MP, Nauseef WM, Griffith TS, Apicella MA. Neisseria gonorrhoeae delays the onset of apoptosis in polymorphonuclear leukocytes. Cell Microbiol. 2006 Nov;8(11):1780-90. Epub 2006 Jun 27.
  4. 4: Vyas PM, Roychowdhury S, Koukouritaki SB, Hines RN, Krueger SK, Williams DE, Nauseef WM, Svensson CK. Enzyme-mediated protein haptenation of dapsone and sulfamethoxazole in human keratinocytes: II. Expression and role of flavin-containing monooxygenases and peroxidases. J Pharmacol Exp Ther. 2006 Oct;319(1):497-505. Epub 2006 Jul 20.
  5. 5: Barker JH, Weiss J, Apicella MA, Nauseef WM. Basis for the failure of Francisella tularensis lipopolysaccharide to prime human polymorphonuclear leukocytes. Infect Immun. 2006 Jun;74(6):3277-84.
  6. 6: Femling JK, Cherny VV, Morgan D, Rada B, Davis AP, Czirjak G, Enyedi P, England SK, Moreland JG, Ligeti E, Nauseef WM, DeCoursey TE. The antibacterial activity of human neutrophils and eosinophils requires proton channels but not BK channels. J Gen Physiol. 2006 Jun;127(6):659-72. Epub 2006 May 15.
  7. 7: Moreland JG, Davis AP, Bailey G, Nauseef WM, Lamb FS. Anion channels, including ClC-3, are required for normal neutrophil oxidative function, phagocytosis, and trans-endothelial migration. J Biol Chem. 2006 May 5;281(18):12277-88. Epub 2006 Mar 7.
  8. 8: Hunt CL, Nauseef WM, Weiss JP. Effect of D-alanylation of (lipo)teichoic acids of Staphylococcus aureus on host secretory phospholipase A2 action before and after phagocytosis by human neutrophils. J Immunol. 2006 Apr 15;176(8):4987-94.
  9. 9: Nauseef WM. Acute oxygen-sensing mechanisms. N Engl J Med. 2006 Mar 2;354(9):975-7; author reply 975-7. No abstract available.

  Environmental Health Sciences Research Center, The University of Iowa, 100 Oakdale Campus, #178 IREH, Iowa City, IA 52242

Tel: (319) 335-4756 / Fax: (319) 335-4225 / E-mail: nancy-newkirk@uiowa.edu