|
|
|
|
|
|
|
|
|||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | |||||
First published online 28 June 2005
doi: 10.1242/jcs.02447
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Research Article |
1 CNRS-UMR8125, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France
2 INSERM U487, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France
3 Institut André Lwoff, INSERM U504, 16 avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France
4 Institute of Biochemistry, University of Kiel, 24098 Kiel, Germany
Author for correspondence (e-mail: kroemer{at}igr.fr)
Accepted 20 April 2005
Autophagic cell death is morphologically characterized by an accumulation of autophagic vacuoles. Here, we show that inactivation of LAMP2 by RNA interference or by homologous recombination leads to autophagic vacuolization in nutrient-depleted cells. Cells that lack LAMP2 expression showed an enhanced accumulation of vacuoles carrying the marker LC3, yet a decreased colocalization of LC3 and lysosomes, suggesting that the fusion between autophagic vacuoles and lysosomes was inhibited. While a fraction of mitochondria from starved LAMP2-expressing cells colocalized with lysosomal markers, within autophagolysosomes, no such colocalization was found on removal of LAMP2 from the experimental system. Of note, LAMP1 depletion had no such effects and did not aggravate the phenotype induced by LAMP2-specific small interfering RNA. Serum and amino acid-starved LAMP2-negative cells exhibited an accumulation of autophagic vacuoles and then succumbed to cell death with hallmarks of apoptosis such as loss of the mitochondrial transmembrane potential, caspase activation and chromatin condensation. While caspase inhibition retarded cell death, it had no protective effect on mitochondria. Stabilization of mitochondria by overexpression of Bcl-2 or the mitochondrion-targeted cytomegalovirus protein vMIA, however, blocked all signs of apoptosis. Neither caspase inhibition nor mitochondrial stabilization antagonized autophagic vacuolization in LAMP2-deficient cells. Altogether, these data indicate that accumulation of autophagic vacuoles can precede apoptotic cell death. These findings argue against the clear-cut distinction between type 1 (apoptotic) and type 2 (autophagic) cell death.
Key words: Bcl-2, caspases, LAMP1, LAMP2, Lysosomes, Mitochondria
Related articles in JCS:
This article has been cited by other articles:
|
|
 |
|
  J. Wong, J. Zhang, X. Si, G. Gao, I. Mao, B. M. McManus, and H. Luo Autophagosome Supports Coxsackievirus B3 Replication in Host Cells J. Virol., September 15, 2008; 82(18): 9143 - 9153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.-S. Yang, A. Kumar, P. Stavrides, J. Peterson, C. M. Peterhoff, M. Pawlik, E. Levy, A. M. Cataldo, and R. A. Nixon Neuronal Apoptosis and Autophagy Cross Talk in Aging PS/APP Mice, a Model of Alzheimer's Disease Am. J. Pathol., September 1, 2008; 173(3): 665 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Nishida, O. Yamaguchi, and K. Otsu Crosstalk Between Autophagy and Apoptosis in Heart Disease Circ. Res., August 15, 2008; 103(4): 343 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Han, W. Hou, L. A. Goldstein, C. Lu, D. B. Stolz, X.-M. Yin, and H. Rabinowich Involvement of Protective Autophagy in TRAIL Resistance of Apoptosis-defective Tumor Cells J. Biol. Chem., July 11, 2008; 283(28): 19665 - 19677. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Singletary and J. Milner Diet, Autophagy, and Cancer: A Review Cancer Epidemiol. Biomarkers Prev., July 1, 2008; 17(7): 1596 - 1610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Apel, I. Herr, H. Schwarz, H. P. Rodemann, and A. Mayer Blocked Autophagy Sensitizes Resistant Carcinoma Cells to Radiation Therapy Cancer Res., March 1, 2008; 68(5): 1485 - 1494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tiwari, V. K. Bajpai, A. A. Sahasrabuddhe, A. Kumar, R. A. Sinha, S. Behari, and M. M. Godbole Inhibition of N-(4-hydroxyphenyl)retinamide-induced autophagy at a lower dose enhances cell death in malignant glioma cells Carcinogenesis, March 1, 2008; 29(3): 600 - 609. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Patschan, J. Chen, A. Polotskaia, N. Mendelev, J. Cheng, D. Patschan, and M. S. Goligorsky Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1119 - H1129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. F. Trincheri, C. Follo, G. Nicotra, C. Peracchio, R. Castino, and C. Isidoro Resveratrol-induced apoptosis depends on the lipid kinase activity of Vps34 and on the formation of autophagolysosomes Carcinogenesis, February 1, 2008; 29(2): 381 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. K. Amaravadi and C. B. Thompson The Roles of Therapy-Induced Autophagy and Necrosis in Cancer Treatment Clin. Cancer Res., December 15, 2007; 13(24): 7271 - 7279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Brabec-Zaruba, U. Berka, D. Blaas, and R. Fuchs Induction of Autophagy Does Not Affect Human Rhinovirus Type 2 Production J. Virol., October 1, 2007; 81(19): 10815 - 10817. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Marsh, C. Soden, C. Alarcon, B. L. Wicksteed, K. Yaekura, A. J. Costin, G. P. Morgan, and C. J. Rhodes Regulated Autophagy Controls Hormone Content in Secretory-Deficient Pancreatic Endocrine {beta}-Cells Mol. Endocrinol., September 1, 2007; 21(9): 2255 - 2269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Liao, Y. Yao, J. Liu, Z. Yu, S. Cheung, A. Xie, X. Liang, and X. Bi Cholesterol Accumulation Is Associated with Lysosomal Dysfunction and Autophagic Stress in Npc1 / Mouse Brain Am. J. Pathol., September 1, 2007; 171(3): 962 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Gonzalez-Polo, M. Niso-Santano, M. A. Ortiz-Ortiz, A. Gomez-Martin, J. M. Moran, L. Garcia-Rubio, J. Francisco-Morcillo, C. Zaragoza, G. Soler, and J. M. Fuentes Inhibition of Paraquat-Induced Autophagy Accelerates the Apoptotic Cell Death in Neuroblastoma SH-SY5Y Cells Toxicol. Sci., June 1, 2007; 97(2): 448 - 458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Demarchi, C. Bertoli, T. Copetti, I. Tanida, C. Brancolini, E.-L. Eskelinen, and C. Schneider Calpain is required for macroautophagy in mammalian cells J. Cell Biol., November 20, 2006; 175(4): 595 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Schaheen, G. Patton, and H. Fares Suppression of the cup-5 mucolipidosis type IV-related lysosomal dysfunction by the inactivation of an ABC transporter in C. elegans Development, October 1, 2006; 133(19): 3939 - 3948. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Massey, S. Kaushik, G. Sovak, R. Kiffin, and A. M. Cuervo Consequences of the selective blockage of chaperone-mediated autophagy PNAS, April 11, 2006; 103(15): 5805 - 5810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fanin, A. C. Nascimbeni, L. Fulizio, M. Spinazzi, P. Melacini, and C. Angelini Generalized Lysosome-Associated Membrane Protein-2 Defect Explains Multisystem Clinical Involvement and Allows Leukocyte Diagnostic Screening in Danon Disease Am. J. Pathol., April 1, 2006; 168(4): 1309 - 1320. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Shacka, B. J. Klocke, M. Shibata, Y. Uchiyama, G. Datta, R. E. Schmidt, and K. A. Roth Bafilomycin A1 Inhibits Chloroquine-Induced Death of Cerebellar Granule Neurons Mol. Pharmacol., April 1, 2006; 69(4): 1125 - 1136. [Abstract] [Full Text] [PDF]
|
|
