SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell-mediated immunity.
SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell-mediated immunity.
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DOI：
10.1126/science.aba4220
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发表时间：
2021-05-14
期刊：
影响因子：
--
通讯作者：
Beutler B
中科院分区：
文献类型：
--
作者：
Yue T;Zhan X;Zhang D;Jain R;Wang KW;Choi JH;Misawa T;Su L;Quan J;Hildebrand S;Xu D;Li X;Turer E;Sun L;Moresco EMY;Beutler B
由同种抗原和共刺激激活的幼稚T细胞可增殖和分化为效应性T细胞。从静息状态到增殖状态的转变需要细胞代谢的深刻变化，特别是糖酵解、谷氨酰胺分解和线粒体代谢的增加，以产生高水平的ATP。T细胞依赖于翻译爆发来产生支持新陈代谢增加的代谢酶，并产生克隆性T细胞后代的蛋白质成分及其细胞因子。矛盾的是，为生长和扩张提供能量的代谢过程也产生了活性氧物种(ROS)，这能够诱导氧化应激导致翻译抑制。另一方面，ROS在T细胞受体(TCR)信号转导中起第二信使的作用，对细胞增殖和效应器功能的发育是必不可少的。这表明，为了保护ROS的信号活性，对氧化应激的保护机制可能发生在多个水平，而不仅仅是降低T细胞中的ROS水平。从小鼠对影响免疫的突变的正向遗传筛查中，我们先前发现了SLFn2的一个隐性突变，导致对细菌和病毒感染的易感性增加，并减少了对感染和各种增殖刺激未能增殖的T细胞的数量。在这里，我们的目的是通过产生T细胞特异性缺失的SLFn2 T细胞特异性缺失的小鼠，使其对T细胞依赖抗原免疫和小鼠巨细胞病毒感染分别表现出受损的体液和细胞免疫反应，从而研究SLFN2在T细胞中的分子功能。这些缺陷源于CD4+和CD8+T细胞对TCR刺激的增殖反应受损，尽管SLFN2缺陷T细胞中TCR信号事件的正常诱导。在TCR刺激后，SLFN2缺陷的T细胞产生IL-2是正常的，但细胞对外源IL-2的反应不能增殖。IL-2R信号转导有缺陷。IL-2促有丝分裂作用的丧失是由于未能在翻译上上调IL-2受体的β和γ链。事实上，在体外和体内，SLFN2缺陷的T细胞对TCR激活的翻译反应是全局受抑的。细胞的氧化应激反应包括由血管生成素(Ang)产生的tRNA片段的翻译抑制，Ang是一种应激诱导的tRNA导向的核糖核酸酶。ANG在其反密码子环内切割tRNA，产生30-40个核苷酸的tRNA片段(TiRNA)。作为对TCR激活的响应，SLFN2缺陷的T细胞积聚了tiRNA，这可以通过抗氧化处理或敲除或抑制Ang来减少。此外，通过抗氧化剂治疗或Ang基因敲除可以挽救激活的SLFN2缺陷T细胞的整体转化率。与其他SLFN蛋白不同，SLFN直接与tRNAs结合，但不对tRNAs产生核溶解活性。SLFN2与tRNAs的结合阻断了Ang对tRNA的切割，从而避免了tiRNA的积累和tiRNA介导的翻译抑制。我们描述了一种保护机制，通过SLFN2保护tRNA免受氧化应激诱导的切割，从而阻止T细胞激活时产生的ROS的翻译抑制效应。重要的是，SLFN2作用于ROS产生本身的下游，使ROS在T细胞代谢和信号转导中的功能保持不变。我们认为血管生成素是一种应激激活的核糖核酸酶，其作用在T细胞中被SLFN2所对抗。我们的数据进一步支持了SLFN家族成员在RNA和翻译调控中的关键作用。活化的T细胞中的活性氧物种(ROS)增加，因为代谢活动被诱导，以支持T细胞的增殖和分化。我们发现，这些ROS触发了氧化应激反应，导致翻译抑制。这种反应被Schlafen 2(SLFN2)所抵消，它直接与tRNA结合，以保护它们不被RNA酶血管生成素(Ang)切割。T细胞特异性SLFN2缺乏会导致tRNA片段的积累，从而抑制翻译并促进应激颗粒的形成。IL-2Rβ和IL-2Rγ在TcR刺激后未能在翻译上上调，导致SLFN_2缺陷T细胞对IL-2‘S促有丝分裂作用不敏感。SLFN2能够抵抗ROS介导的翻译抑制效应，正常情况下是由T细胞激活诱导的氧化应激，允许强大的蛋白质合成，是T细胞扩张和免疫所必需的。SLFN2通过保护tRNA不被Ang切割来支持激活的T细胞的翻译，以响应氧化应激。
Naïve T cells activated by cognate antigens and co-stimulation proliferate and differentiate to effector T cells. The shift from a resting to a proliferative state entails profound changes in cellular metabolism, in particular increases in glycolysis, glutaminolysis, and mitochondrial metabolism, to produce high levels of ATP. T cells depend on a translational burst to produce the metabolic enzymes that support an increase in metabolism, and to produce the protein components of clonal T cell progeny and their cytokines. Paradoxically, the metabolic processes that provide energy for growth and expansion also produce reactive oxygen species (ROS), which are capable of inducing oxidative stress that leads to translation repression. On the other hand, ROS function as second messengers in T cell receptor (TCR) signaling and are essential for proliferation and development of effector function. This suggests that in order to preserve the signaling activities of ROS, protective mechanisms against oxidative stress may occur at multiple levels beyond simply reducing ROS levels in T cells. From a mouse forward genetic screen for mutations affecting immunity, we previously identified a recessive mutation in Slfn2, leading to elevated susceptibility to bacterial and viral infections, and diminished numbers of T cells that failed to proliferate in response to infection and diverse proliferative stimuli. Here, we aimed to investigate the molecular function of SLFN2 in T cells by generating mice with a T cell-specific deletion of Slfn2 T cell-specific SLFN2-deficient mice displayed compromised humoral and cellular immune responses to immunization with a T cell-dependent antigen and to infection with mouse cytomegalovirus, respectively. These defects stemmed from impaired CD4+ and CD8+ T cell proliferative responses to TCR stimulation, despite normal induction of TCR signaling events in SLFN2-deficient T cells. Whereas IL-2 production by SLFN2-deficient T cells was normal after TCR stimulation, the cells failed to proliferate in response to exogenous IL-2. IL-2R signaling was defective. Abrogation of the mitogenic effects of IL-2 was due to a failure to translationally upregulate the β and γ chains of the IL-2 receptor. Indeed, there was a globally dampened translational response to TCR activation in SLFN2-deficient T cells in vitro and in vivo. The cellular oxidative stress response includes translation repression by tRNA fragments generated by angiogenin (ANG), a stress-induced tRNA-directed RNase. ANG cleaves tRNAs within their anticodon loops, yielding 30–40-nucleotide tRNA fragments (tiRNA). In response to TCR activation, SLFN2-deficient T cells accumulated tiRNA, which could be reduced by antioxidant treatment or knockdown or inhibition of ANG. Moreover, global translation rates in activated SLFN2-deficient T cells could be rescued by antioxidant treatment or by ANG knockdown. SLFN2 directly bound to tRNAs, but exerted no nucleolytic activity towards them, unlike other SLFN proteins. Binding of SLFN2 to tRNAs blocked tRNA cleavage by ANG, thereby averting tiRNA accumulation and tiRNA-mediated translation repression. We describe a protective mechanism by which SLFN2 shields tRNA from oxidative stress-induced cleavage, thereby preventing the translation inhibitory effects of ROS produced in response to T cell activation. Importantly, SLFN2 acts downstream of ROS production itself, leaving ROS functions in T cell metabolism and signaling intact. We identify angiogenin as a stress-activated RNase whose effects are opposed by SLFN2 in T cells. Our data provide further support for a key role of SLFN family members in the regulation of RNA and translation. Reactive oxygen species (ROS) increase in activated T cells because of metabolic activity induced to support T cell proliferation and differentiation. We show that these ROS trigger an oxidative stress response leading to translation repression. This response is countered by Schlafen 2 (SLFN2), which directly binds tRNAs to protect them from cleavage by the RNase angiogenin (ANG). T cell-specific SLFN2 deficiency results in the accumulation of tRNA fragments, which inhibit translation and promote stress granule formation. IL-2Rβ and IL-2Rγ fail to be translationally upregulated following TCR stimulation, rendering SLFN2-deficient T cells insensitive to IL-2’s mitogenic effects. SLFN2 confers resistance against the ROS-mediated translation-inhibitory effects of oxidative stress normally induced by T cell activation, permitting robust protein synthesis necessary for T cell expansion and immunity. SLFN2 upholds translation in activated T cells by protecting tRNA from cleavage by ANG in response to oxidative stress.
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影响因子：
14.9
作者：
Chan PP;Lowe TM
通讯作者：
Lowe TM
影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
DOI：
10.1111/febs.12071
发表时间：
2013-01
期刊：
The FEBS journal
影响因子：
--
作者：
Iyer S;Holloway DE;Acharya KR
通讯作者：
Acharya KR
影响因子：
2.9
作者：
FETT, JW;STRYDOM, DJ;VALLEE, BL
通讯作者：
VALLEE, BL
影响因子：
4.5
作者：
Fletcher, Sarah J.;Pisareva, Vera P.;Pisarev, Andrey, V
通讯作者：
Pisarev, Andrey, V