N. Tony Eissa, M.D.
Professor of Medicine, Immunology and Molecular Cell Biology
Baylor College of Medicine
One Baylor Plaza - BCM285
Houston, Texas 77030
- M.D., Tanta Faculty of Medicine, Tanta, Egypt
- Postdoctoral Training, NHLBI, NIH, Bethesda, Md.
Signaling pathways for atuophagy associated with innate imminity and cellular regulation of misfolded proteins
Regulation of Autophagy in Innate Immunity
Our work on autophagy involves determining the molecular pathways regulating autophagy during pathogen infection. Autophagy has been recently shown to be an important component of the innate immune response by degrading foreign microbial invaders. The upstream signaling pathways leading to activation of autophagy are not known and currently under investigation in our laboratory. Our recent study links autophagy to innate immunity Toll-like receptor 4 (TLR4). Further, it defines the signaling pathway downstream from TLR4 via TRIF/RIP1/p38MAPK. This pathway maintains cell survival in the context of autophagy associated with infection and is distinct from autophagic cell death. The potential therapeutic use of modulating this pathway is significant. As a proof of concept, we used LPS treatment to force mycobacterium tuberculosis to the autophagosomes and to be lysed by the lysosomes.
Cellular Regulation of Nitric Oxide Synthesis in Inflammation
Our laboratory is credited with several key discoveries for the regulation of iNOS. These discoveries included regulation of iNOS by alternative mRNA splicing, elucidation of structural domains required for iNOS activity and dimerization, determination of key residues in iNOS structure needed to control its activity and substrate binding, identifying the degradation pathway for iNOS, elucidating iNOS regulation by ubiquitination, determining the rate of cellular iNOS turnover and discovering the translational inhibition of iNOS by dimerization inhibitors. In addition, we have recently shown that iNOS forms what we termed the ‘physiologic aggresome”. Previously the aggresome has been thought to represent a sequestration of misfolded proteins. Thus, iNOS aggresome defines a new paradigm for cellular regulation of protein processing. This extensive work on the mechanisms of iNOS regulation has increased our understanding of iNOS biology and has laid the ground work for potential breakthroughs both in understanding iNOS regulation as well in devising novel strategies to regulate iNOS in diseases characterized by over production of NO. The work on iNOS extends our observations to how cells regulate protein trafficking between the proteasome (for degradation) and the aggresome (as a holding station). Thus, the significance of the work involves many pathological conditions including lung inflammation and fibrosis, cardiovascular shock, and stroke and neurodegenerative diseases.
Cellular Regulation of Misfolded Proteins
Our work with both autophagy and iNOS has revealed several important insights into how cells regulate protein trafficking and homeostasis under physiologic and pathologic conditions. Current projects on our laboratory focus on signaling pathway and regulatory proteins that regulate these processes. Specifically, we would like to determine how cells switch proteins among proteasome, aggresome and autophagy pathways. In addition, we are studying various cellular responses and consequences of the presence of misfolded proteins known to associate with human diseases such as in cystic fibrosis and alpha-1 antitrypsin related diseases.
Awards and Honors
- Pfizer Visiting Professorship in Pulmonolgy, 2006
- Pfizer Visiting Professorship in Allergic Diseases and Asthma, 2004
- Independent Scientist Award, NIAID, NIH, 2003
- Scientist Development Award, American Heart Association, 2002
- Career Investigator Award, American Lung Association, 2002
- NIH Award for Research Excellence, 1997
- Tyryshkin A, Gorgun FM, Abdel Fattah E, Mazumdar T, Pandit L, Zeng S, Eissa NT. SRC kinase-mediated phosphorylation stabilizes iNOS in normal and in cancer cells. J Biol Chem. 2010; 285:784-92.
- Jagannath C, Lindsey DR, Dhandayuthapani S, Xu Y, Hunter RL Jr, Eissa NT. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med. 2009; 15(3):267-76.
- Liu XD, Mazumdar T, Xu Y, Getzoff ED, Eissa NT. Identification of a flavin mononucleotide module residue critical for activity of inducible nitrite oxide synthase. J Immunol. 2009; 183(9):5977-82.
- Pandit L, Kolodziejska KE, Zeng S, Eissa NT. The physiologic aggresome mediates cellular inactivation of iNOS. Proc Natl Acad Sci U S A. 2009; 106(4):1211-5.
- Sha Y, Pandit L, Zeng S, Eissa NT. A critical role for CHIP in the aggresome pathway. Mol Cell Biol. 2009; 29(1):116-28.
- Xu Y, Jagannath C, Liu XD, Sharafkhaneh A, Kolodziejska KE, Eissa NT. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity. 2007; 27(1):135-44.
- Kolodziejska KE, Burns AR, Moore RH, Stenoien DL, Eissa NT. Regulation of inducible nitric oxide synthase by aggresome formation. Proc Natl Acad Sci U S A. 2005; 102(13):4854-9.
- Mazumdar T, Eissa NT. Preferential recognition of undisruptable dimers of inducible nitric oxide synthase by a monoclonal antibody directed against an N-terminal epitope. J Immunol. 2005; 174(4):2314-7.
- Kolodziejski PJ, Koo JS, Eissa NT. Regulation of inducible nitric oxide synthase by rapid cellular turnover and cotranslational down-regulation by dimerization inhibitors. Proc Natl Acad Sci U S A. 2004; 101(52):18141-6.
- Kolodziejski PJ, Rashid MB, Eissa NT. Intracellular formation of "undisruptable" dimers of inducible nitric oxide synthase. Proc Natl Acad Sci U S A. 2003; 100(24):14263-8.