title: Temporal regulation of intracellular organelle homeostasis in T lymphocytes by autophagy.
abstract: The highly conserved self-degradation pathway known as autophagy plays important roles in regulating T lymphocyte homeostasis. Recently, we found that T lymphocytes lacking the autophagy-related gene Atg5 or Atg7 have defective survival and contain expanded mitochondria and endoplasmic reticulum (ER); however, whether these defects are caused by impaired autophagy or by defects in their autophagy-independent signaling capacity of Atg5 or Atg7 in T lymphocytes remains unknown. Furthermore, the function of the microtubule-associated protein L chain 3 (LC3) conjugation system in T lymphocytes remains unclear. To address these questions, we generated conditional knockout mice with specific deletion of Atg3, a ubiquitin enzyme E2-like molecule involved in the LC3 conjugation system, in T lymphocytes. Atg3-deficient T lymphocytes displayed a phenotype similar to those of Atg7- and Atg5-deficient T cells. The survival of Atg3-deficient naive CD4(+) and CD8(+) T cells was defective. Furthermore, the mitochondria and ER were expanded in Atg3-deficient T cells. Interestingly, mitochondrial and ER content did not change instantly upon inducible deletion of Atg3 in mature T lymphocytes in vitro. Instead, it began to expand 10 d after inducible deletion of Atg3 in mature T lymphocytes, and mitochondrial content continued to increase on day 18. Cell death began to increase 24 d after inducible deletion of Atg3. These data show that the LC3 conjugation system is essential for autophagy in T lymphocytes. Our data suggest that autophagy promotes T lymphocyte survival by regulating organelle homeostasis and that the decreased survival of autophagy-deficient T cells is due to the temporal accumulation of these autophagy-related defects.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D005260:Female; D005434:Flow Cytometry; D006706:Homeostasis / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism; D015388:Organelles / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
chemical_list: C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins