Departments of Pediatrics, Developmental Biology and Cell Biology and Physiology, University of Pittsburgh School of Medicine; John G. Rangos Sr. Research Center, Room 7129, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
Magee-Womens Research Institute, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA, 15213, USA.
Nat Commun. 2019 Jul 17;10(1):3042. doi: 10.1038/s41467-019-10759-z.
Stress resistance and longevity are positively correlated but emerging evidence indicates that they are physiologically distinct. Identifying factors with distinctive roles in these processes is challenging because pro-longevity genes often enhance stress resistance. We demonstrate that TCER-1, the Caenorhabditis elegans homolog of human transcription elongation and splicing factor, TCERG1, has opposite effects on lifespan and stress resistance. We previously showed that tcer-1 promotes longevity in germline-less C. elegans and reproductive fitness in wild-type animals. Surprisingly, tcer-1 mutants exhibit exceptional resistance against multiple stressors, including infection by human opportunistic pathogens, whereas, TCER-1 overexpression confers immuno-susceptibility. TCER-1 inhibits immunity only during fertile stages of life. Elevating its levels ameliorates the fertility loss caused by infection, suggesting that TCER-1 represses immunity to augment fecundity. TCER-1 acts through repression of PMK-1 as well as PMK-1-independent factors critical for innate immunity. Our data establish key roles for TCER-1 in coordinating immunity, longevity and fertility, and reveal mechanisms that distinguish length of life from functional aspects of aging.
应激抗性和寿命呈正相关，但新出现的证据表明它们在生理上是不同的。确定在这些过程中具有独特作用的因素具有挑战性，因为延长寿命的基因通常会增强应激抗性。我们证明，秀丽隐杆线虫人类转录延伸和剪接因子 TCERG1 的同源物 TCER-1，对寿命和应激抗性有相反的影响。我们之前曾表明，tcer-1 可促进无生殖系的秀丽隐杆线虫的长寿和野生型动物的生殖适应性。令人惊讶的是，tcer-1 突变体对多种应激源表现出异常的抗性，包括人类机会性病原体的感染，而 TCER-1 的过表达会导致免疫敏感性。TCER-1 仅在有生育能力的生命阶段抑制免疫。提高其水平可以减轻感染引起的生育力丧失，表明 TCER-1 抑制免疫以增加繁殖力。TCER-1 通过抑制 PMK-1 以及对先天免疫至关重要的 PMK-1 非依赖性因素来发挥作用。我们的数据确立了 TCER-1 在协调免疫、寿命和生育力方面的关键作用，并揭示了区分寿命和衰老功能方面的机制。
