The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20-/- cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20-/- cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis.

中文翻译：

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泛素编辑酶A20通过调节mTOR活性和TNF来控制NK细胞的稳态。

泛素编辑酶A20是免疫细胞功能和体内平衡的众所周知的调节剂。另外，A20以不确定的方式保护细胞免于死亡。虽然大多数研究都集中在它在TNF受体复合物中的作用，但我们在这里确定了A20介导的生死决定中的新成分。NK细胞中A20的丢失导致自发性NK细胞死亡和严重的NK细胞淋巴细胞减少。剩下的少数NK细胞表现出不成熟的，过度活化的表型，其特征在于细胞因子和细胞毒性分子的基础释放。NK-A20-/-细胞对TNF诱导的细胞死亡高度敏感，可以通过与TNF联合缺乏而至少部分地得到挽救。出乎意料的是，雷帕霉素（一种公认的mTOR抑制剂）也强烈保护NK-A20-/-细胞免于死亡，进一步的研究表明，A20会限制NK细胞中的mTOR活化。因此，本研究将A20定位为mTOR信号的关键调节剂，并强调了NK细胞稳态中紧密平衡的mTOR途径的需求。