TITLE

Toxoplasma gondii-Induced Activation of EGFR Prevents Autophagy Protein-Mediated Killing of the Parasite

AUTHOR(S)
Muniz-Feliciano, Luis; Van Grol, Jennifer; Portillo, Jose-Andres C.; Liew, Lloyd; Liu, Bing; Carlin, Cathleen R.; Carruthers, Vern B.; Matthews, Stephen; Subauste, Carlos S.
PUB. DATE
December 2013
SOURCE
PLoS Pathogens;Dec2013, Vol. 9 Issue 12, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Toxoplasma gondii resides in an intracellular compartment (parasitophorous vacuole) that excludes transmembrane molecules required for endosome - lysosome recruitment. Thus, the parasite survives by avoiding lysosomal degradation. However, autophagy can re-route the parasitophorous vacuole to the lysosomes and cause parasite killing. This raises the possibility that T. gondii may deploy a strategy to prevent autophagic targeting to maintain the non-fusogenic nature of the vacuole. We report that T. gondii activated EGFR in endothelial cells, retinal pigment epithelial cells and microglia. Blockade of EGFR or its downstream molecule, Akt, caused targeting of the parasite by LC3+ structures, vacuole-lysosomal fusion, lysosomal degradation and killing of the parasite that were dependent on the autophagy proteins Atg7 and Beclin 1. Disassembly of GPCR or inhibition of metalloproteinases did not prevent EGFR-Akt activation. T. gondii micronemal proteins (MICs) containing EGF domains (EGF-MICs; MIC3 and MIC6) appeared to promote EGFR activation. Parasites defective in EGF-MICs (MIC1 ko, deficient in MIC1 and secretion of MIC6; MIC3 ko, deficient in MIC3; and MIC1-3 ko, deficient in MIC1, MIC3 and secretion of MIC6) caused impaired EGFR-Akt activation and recombinant EGF-MICs (MIC3 and MIC6) caused EGFR-Akt activation. In cells treated with autophagy stimulators (CD154, rapamycin) EGFR signaling inhibited LC3 accumulation around the parasite. Moreover, increased LC3 accumulation and parasite killing were noted in CD154-activated cells infected with MIC1-3 ko parasites. Finally, recombinant MIC3 and MIC6 inhibited parasite killing triggered by CD154 particularly against MIC1-3 ko parasites. Thus, our findings identified EGFR activation as a strategy used by T. gondii to maintain the non-fusogenic nature of the parasitophorous vacuole and suggest that EGF-MICs have a novel role in affecting signaling in host cells to promote parasite survival.
ACCESSION #
93395291

 

Related Articles

  • EGFR-Targeted Hybrid Plasmonic Magnetic Nanoparticles Synergistically Induce Autophagy and Apoptosis in Non-Small Cell Lung Cancer Cells. Yokoyama, Tomohisa; Tam, Justina; Kuroda, Shinji; Scott, Ailing W.; Aaron, Jesse; Larson, Tim; Shanker, Manish; Correa, Arlene M.; Kondo, Seiji; Roth, Jack A.; Sokolov, Konstantin; Ramesh, Rajagopal // PLoS ONE;2011, Vol. 6 Issue 11, p1 

    Background: The epidermal growth factor receptor (EGFR) is overexpressed in 80% of non-small cell lung cancer (NSCLC) and is associated with poor survival. In recent years, EGFR-targeted inhibitors have been tested in the clinic for NSCLC. Despite the emergence of novel therapeutics and their...

  • Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells. Sakuma, Yuji; Matsukuma, Shoichi; Nakamura, Yoshiyasu; Yoshihara, Mitsuyo; Koizume, Shiro; Sekiguchi, Hironobu; Saito, Haruhiro; Nakayama, Haruhiko; Kameda, Yoichi; Yokose, Tomoyuki; Oguni, Sachiko; Niki, Toshiro; Miyagi, Yohei // Laboratory Investigation (00236837);Oct2013, Vol. 93 Issue 10, p1137 

    Lung cancers harboring epidermal growth factor receptor (EGFR) mutations depend on constitutive activation of the kinase for survival. Although most EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs) and shrink in response to treatment, acquired resistance to TKI...

  • Induction of Autophagy Is an Early Response to Gefitinib and a Potential Therapeutic Target in Breast Cancer. Dragowska, Wieslawa H.; Weppler, Sherry A.; Wang, Jun Chih; Wong, Ling Yan; Kapanen, Anita I.; Rawji, Jenna S.; Warburton, Corinna; Qadir, Mohammed A.; Donohue, Elizabeth; Roberge, Michel; Gorski, Sharon M.; Gelmon, Karen A.; Bally, Marcel B. // PLoS ONE;Oct2013, Vol. 8 Issue 10, p1 

    Gefitinib (Iressa®, ZD1839) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. We report on an early cellular response to gefitinib that involves induction of functional autophagic flux in phenotypically diverse breast cancer cells that were...

  • Autophagy Protein Atg3 is Essential for Maintaining Mitochondrial Integrity and for Normal Intracellular Development of Toxoplasma gondii Tachyzoites. Besteiro, Sébastien; Brooks, Carrie F.; Striepen, Boris; Dubremetz, Jean-François // PLoS Pathogens;Dec2011, Vol. 7 Issue 12, Special section p1 

    Autophagy is a cellular process that is highly conserved among eukaryotes and permits the degradation of cellular material. Autophagy is involved in multiple survival-promoting processes. It not only facilitates the maintenance of cell homeostasis by degrading long-lived proteins and damaged...

  • Autophagosome-Mediated EGFR Down-Regulation Induced by the CK2 Inhibitor Enhances the Efficacy of EGFR-TKI on EGFR-Mutant Lung Cancer Cells with Resistance by T790M. So, Kwang Sup; Kim, Cheol Hyeon; Rho, Jin Kyung; Kim, Sun Ye; Choi, Yun Jung; Song, Joon Seon; Kim, Woo Sung; Choi, Chang Min; Chun, Young Jin; Lee, Jae Cheol // PLoS ONE;Dec2014, Vol. 9 Issue 12, p1 

    Protein kinase CK2 has diverse functions promoting and maintaining cancer phenotypes. We investigated the effect of CK2 inhibition in lung cancer cells with T790M-mediated resistance to the EGFR-TK inhibitor. Resistant sublines of PC-9 to gefitinib (PC-9/GR) and erlotinib (PC-9/ER) were...

  • Structural biology: E2 loader. Donner, Amy // Nature Chemical Biology;Dec2012, Vol. 9 Issue 1, p8 

    The article discusses a cellular process called autophagy in which cytoplasm is engulfed by a double-membrane vesicle which further fuses with the lysosome.

  • Autophagy: Eating up damaged lysosomes. Wrighton, Katharine H. // Nature Reviews Molecular Cell Biology;Aug2013, Vol. 14 Issue 8, p465 

    The article offers information on a study conducted by researcher Y.H. Hung and colleagues which reveals that autophagosomes help in degrading lysosomes.

  • Cotargeting EGFR and autophagy signaling: A novel therapeutic strategy for non-small-cell lung cancer (Review). XINBING SUI; NA KONG; MINGHUA ZHU; XIAN WANG; FANG LOU; WEIDONG HAN; HONGMING PAN // Molecular & Clinical Oncology;2014, Vol. 2 Issue 1, p8 

    Epidermal growth factor receptor(EGFR) somatic mutations are found in the majority of non-small-cell lung cancers(NSCLCs) and patients with NSCLC who harbor EGFR mutations have been shown to exhibit increased sensitivity to the small-molecule EGFR-tyrosine kinase inhibitors (TKIs) gefitinib and...

  • CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. Andrade, Rosa M.; Wessendarp, Matthew; Gubbels, Marc-Jan; Striepen, Boris; Subauste, Carlos S. // Journal of Clinical Investigation;Sep2006, Vol. 116 Issue 9, p2366 

    Many intracellular pathogens, including Toxoplasma gondii, survive within macrophages by residing in vacuoles that avoid fusion with lysosomes. It is important to determine whether cell-mediated immunity can trigger macrophage antimicrobial activity by rerouting these vacuoles to lysosomes. We...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics