SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity

doi:10.1126/science.aba4220

GSTDTAP > 气候变化

DOI	10.1126/science.aba4220
	SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity
	Tao Yue; Xiaoming Zhan; Duanwu Zhang; Ruchi Jain; Kuan-wen Wang; Jin Huk Choi; Takuma Misawa; Lijing Su; Jiexia Quan; Sara Hildebrand; Darui Xu; Xiaohong Li; Emre Turer; Lei Sun; Eva Marie Y. Moresco; Bruce Beutler
	2021-05-14
发表期刊	Science
出版年	2021
英文摘要	Considerable changes in cellular metabolism occur when T cells transition from a resting to an activated state. One side effect of this process is an increase in reactive oxygen species (ROS). These molecules potentiate T cell receptor (TCR) signaling but can also result in detrimental oxidative stress (see the Perspective by Su and Dutta). Yue et al. describe one mechanism by which T cells can resolve this contradiction. Using mice with a T cell-specific deficiency in Schlafen 2 (SLFN2), they found that this protein binds to and protects transfer RNAs from oxidative stress-induced cleavage by the ribonuclease angiogenin. This process is downstream of ROS generation, which allows activated T cells to maintain protein synthesis despite the ROS that would otherwise inhibit translation. Science , this issue p. [eaba4220][1]; see also p. [683][2] ### INTRODUCTION Naïve T cells activated by cognate antigens and costimulation 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 adenosine 5′-triphosphate (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). These are capable of inducing oxidative stress, which leads to the repression of translation. 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 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. ### RATIONALE From a mouse-forward genetic screen for mutations affecting immunity, we previously identified a recessive mutation in the Schlafen 2 ( Slfn2 ) gene, which leads to elevated susceptibility to bacterial and viral infections and to 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 . ### RESULTS 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. Interleukin-2 (IL-2) production by SLFN2-deficient T cells was normal after TCR stimulation, but these cells failed to proliferate in response to exogenous IL-2, which suggests that interleukin-2 receptor (IL-2R) signaling was defective. The abrogation of the mitogenic effects of IL-2 was a result of a failure to translationally up-regulate the β and γ chains of the IL-2 receptor. There was a globally dampened translational response to TCR activation in SLFN2-deficient T cells both in vitro and in vivo. The cellular oxidative stress response includes translation repression by transfer RNA (tRNA) fragments generated by angiogenin (ANG), a stress-induced tRNA-directed ribonuclease (RNase). ANG cleaves tRNAs within their anticodon loops, yielding 30- to 40-nucleotide tRNA fragments (tiRNAs). In response to TCR activation, SLFN2-deficient T cells accumulated tiRNA, which could be reduced by antioxidant treatment or by 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 it exerted no nucleolytic activity toward them, unlike other SLFN proteins. Binding of SLFN2 to tRNAs blocked tRNA cleavage by ANG, thereby averting tiRNA accumulation and tiRNA-mediated translation repression. ### CONCLUSION 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. Notably, SLFN2 acts downstream of ROS production itself, leaving ROS functions in T cell metabolism and signaling intact. We identify ANG 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. ![Figure][3] SLFN2 protects tRNA from oxidative stress–induced cleavage, precluding translation inhibition by tRNA fragments (tiRNA). T cell–specific SLFN2 deficiency results in excessive tRNA cleavage mediated by the oxidative stress–activated ribonuclease ANG during the metabolic reprogramming phase of activated T cells. Accumulated tiRNA promotes stress-granule assembly and inhibits translation by displacing eukaryotic initiation factors (eIFs) from mRNA. SLFN2-deficient T cells fail to translationally up-regulate IL-2Rβ and IL-2Rγ. MHC, major histocompatibility complex; APC, antigen-presenting cell; TCA, tricarboxylic acid. 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 that leads to translation repression. This response is countered by Schlafen 2 (SLFN2), which directly binds transfer RNAs (tRNAs) to protect them from cleavage by the ribonuclease angiogenin. T cell–specific SLFN2 deficiency results in the accumulation of tRNA fragments, which inhibit translation and promote stress-granule formation. Interleukin-2 receptor β (IL-2Rβ) and IL-2Rγ fail to be translationally up-regulated after T cell receptor stimulation, rendering SLFN2-deficient T cells insensitive to interleukin-2’s mitogenic effects. SLFN2 confers resistance against the ROS-mediated translation-inhibitory effects of oxidative stress normally induced by T cell activation, permitting the robust protein synthesis necessary for T cell expansion and immunity. [1]: /lookup/doi/10.1126/science.aba4220 [2]: /lookup/doi/10.1126/science.abi7265 [3]: pending:yes
领域	气候变化 ; 资源环境
URL	查看原文
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/326811
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Tao Yue,Xiaoming Zhan,Duanwu Zhang,等. SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity[J]. Science,2021.
APA	Tao Yue.,Xiaoming Zhan.,Duanwu Zhang.,Ruchi Jain.,Kuan-wen Wang.,...&Bruce Beutler.(2021).SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity.Science.
MLA	Tao Yue,et al."SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity".Science (2021).