泛素结合蛋白TAX1BP1介导自噬体的诱导及活化T细胞的代谢转变。
The Ubiquitin Binding Protein TAX1BP1 Mediates Autophagasome Induction and the Metabolic Transition of Activated T Cells.
作者信息
Whang Michael I, Tavares Rita M, Benjamin Daniel I, Kattah Michael G, Advincula Rommel, Nomura Daniel K, Debnath Jayanta, Malynn Barbara A, Ma Averil
机构信息
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0358, USA.
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
出版信息
Immunity. 2017 Mar 21;46(3):405-420. doi: 10.1016/j.immuni.2017.02.018. Epub 2017 Mar 14.
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 G 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.
在免疫反应过程中，初始T细胞从小的静止细胞转变为快速循环的细胞。我们发现，缺乏TAX1BP1的T细胞在细胞大小增长和细胞周期循环方面出现延迟。TAX1BP1缺陷型T细胞退出G期，但停滞在S期，这是由于生物能量和生物合成缺陷所致。这些缺陷是由于mTOR复合物形成和激活不足。而这些mTOR缺陷又是由自噬诱导缺陷导致的。TAX1BP1通过其LC3相互作用区域（LIR）与LC3和GABARAP结合，但不是通过其泛素结合结构域，从而支持T细胞增殖。用代谢活性的L-半胱氨酸补充TAX1BP1缺陷型T细胞可挽救mTOR激活和增殖，但不能挽救自噬。这些研究表明，TAX1BP1驱动一种特殊形式的自噬，提供关键氨基酸来激活mTOR并实现活化T细胞的代谢转变。
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