Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence
Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence
复制标题
多胺控制 eIF5A 抑制、TFEB 翻译和自噬以逆转 B 细胞衰老
DOI：
10.1016/j.molcel.2019.08.005
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发表时间：
2019-10-03
期刊：
影响因子：
16
通讯作者：
Simon, Anna Katharina
中科院分区：
文献类型：
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作者：
Zhang, Hanlin;Alsaleh, Ghada;Simon, Anna Katharina
不能产生适应性免疫反应是衰老的标志。B细胞功能降低导致疫苗接种效果差，老年人感染率高。本研究表明，自噬减少是免疫衰老的核心分子机制。成熟淋巴细胞的自噬水平特异性降低，导致老年人记忆B细胞反应受损。亚精胺是一种内源性多胺代谢物，在体内诱导自噬并恢复记忆B细胞反应。从机制上讲，亚精胺翻译后修饰翻译因子eIF5A，这对于自噬转录因子TFEB的合成至关重要。亚精胺在老年人中减少，导致TFEB表达减少和自噬。补充亚精胺恢复了这一途径，并改善了衰老的人B细胞的反应。综上所述，我们的研究结果揭示了eIF5A在翻译水平上介导的一种意想不到的自噬调节机制，可以用来逆转人类的免疫衰老。
Failure to make adaptive immune responses is a hallmark of aging. Reduced B cell function leads to poor vaccination efficacy and a high prevalence of infections in the elderly. Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor TFEB. Spermidine is depleted in the elderly, leading to reduced TFEB expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans.