The Ubiquitin Binding Protein TAX1BP1 Mediates Autophagasome Induction and the Metabolic Transition of Activated T Cells.
During immune responses, naive T cells transition from small quiescent cells to rapidly cycling cells. We have found that T cells lacking TAX1BP1 exhibit delays in growth of cell size and cell cycling. TAX1BP1-deficient T cells exited G0but stalled in S phase, due to both bioenergetic and biosynthetic defects. These defects were due to deficiencies in mTOR complex formation and activation. These mTOR defects in turn resulted from defective autophagy induction. TAX1BP1 binding of LC3 and GABARAP via its LC3-interacting region (LIR), but not its ubiquitin-binding domain, supported T cell proliferation. Supplementation of TAX1BP1-deficient T cells with metabolically active L-cysteine rescued mTOR activation and proliferation but not autophagy. These studies reveal that TAX1BP1 drives a specialized form of autophagy, providing critical amino acids that activate mTOR and enable the metabolic transition of activated T cells.
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0358, USA.
Michael I
MI
Whang
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0358, USA.
Rita M
RM
Tavares
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Daniel I
DI
Benjamin
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0358, USA.
Michael G
MG
Kattah
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0358, USA.
Rommel
R
Advincula
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Daniel K
DK
Nomura
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143-0505, USA.
Jayanta
J
Debnath
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0358, USA.
Barbara A
BA
Malynn
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0358, USA. Electronic address: averil.ma@ucsf.edu.
Averil
A
Ma
D000818:Animals; D000071182:Autophagosomes / Q000276:immunology* / Q000378:metabolism; D001343:Autophagy / Q000276:immunology; D002469:Cell Separation; D022202:Chromosomes, Artificial, Bacterial; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C523855:TAX1BP1 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
LC3; selective autophagy; ubiquitin