The Ubiquitin Binding Protein TAX1BP1 Mediates Autophagosome Induction and the Metabolic Transition of Activated T Cells

• DOI: 10.1016/j.immuni.2017.02.018
• Publication Date: 2017-03-14T16:19:38Z
• Authors: Michael I. Whang; Rita M. Tavares; Daniel I. Benjamin; Michael G. Kattah; Rommel Advincula; Daniel K. Nomura; Jayanta Debnath; Barbara A. Malynn; Averil Ma
• Keywords: Chromosomes, Artificial, Bacterial; 1.1 Normal biological development and functioning; Knockout; T-Lymphocytes; Immunology; 610; Cell Separation; Inbred C57BL; Lymphocyte Activation; Chromosomes; Mice; 03 medical and health sciences; ubiquitin; LC3; Autophagy; 2.1 Biological and endogenous factors; Animals; selective autophagy; Mice, Knockout; 0303 health sciences; Biomedical and Clinical Sciences; TOR Serine-Threonine Kinases; Bacterial; Autophagosomes; Intracellular Signaling Peptides and Proteins; Neoplasm Proteins; Mice, Inbred C57BL; Artificial; Generic health relevance

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 G0 but 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.