Identification of Atg5-dependent transcriptional changes and increases in mitochondrial mass in Atg5-deficient T lymphocytes.
Autophagy is implicated in many functions of mammalian cells such as organelle recycling, survival and differentiation, and is essential for the maintenance of T and B lymphocytes. Here, we demonstrate that autophagy is a constitutive process during T cell development. Deletion of the essential autophagy genes Atg5 or Atg7 in T cells resulted in decreased thymocyte and peripheral T cell numbers, and Atg5-deficient T cells had a decrease in cell survival. We employed functional-genetic and integrative computational analyses to elucidate specific functions of the autophagic process in developing T-lineage lymphocytes. Our whole-genome transcriptional profiling identified a set of 699 genes differentially expressed in Atg5-deficient and Atg5-sufficient thymocytes (Atg5-dependent gene set). Strikingly, the Atg5-dependent gene set was dramatically enriched in genes encoding proteins associated with the mitochondrion. In support of a role for autophagy in mitochondrial maintenance in T lineage cells, the deletion of Atg5 led to increased mitochondrial mass in peripheral T cells. We also observed a correlation between mitochondrial mass and Annexin-V staining in peripheral T cells. We propose that autophagy is critical for mitochondrial maintenance and T cell survival. We speculate that, similar to its role in yeast or mammalian liver cells, autophagy is required in T cells for the removal of damaged or aging mitochondria and that this contributes to the cell death of autophagy-deficient T cells.
Stephenson
Linda M
LM
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Miller
Brian C
BC
Ng
Aylwin
A
Eisenberg
Jason
J
Zhao
Zijiang
Z
Cadwell
Ken
K
Graham
Daniel B
DB
Mizushima
Noboru N
NN
Xavier
Ramnik
R
Virgin
Herbert W
HW
Swat
Wojciech
W
D000818:Animals; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D019295:Computational Biology; D030541:Databases, Genetic; D016678:Genome / Q000235:genetics; D019426:Integrases / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D053142:Mitochondrial Size; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D014158:Transcription, Genetic
C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; C045073:Cre recombinase; D019426:Integrases; D000071193:Autophagy-Related Protein 7