Role of the transcription elongation and splicing factor TCER-1 in repressing immunity and promoting fertility

摘要

ABSTRACT Fat is a vital cellular resource for both reproduction and immunity. Both the bulk availability of lipids and specif- ic lipid species influence fertility and immunity as they act as energy source and signaling molecules, respec- tively. There is ample evidence that differential fat allocation impacts the health of both women and men. Thus, lipid metabolism is inextricably linked to immunity and fertility, but the underlying molecular connections are poorly understood. These are challenging to address in long-lived, slow-reproducing mammalian models. Cae- norhabditis elegans is especially valuable for studying the role of lipids in driving the immunity-fertility relation- ship due to its high reproductive rate, and because in worms the deposition of maternal fat into oocytes can be easily visualized, assessed and manipulated. This proposal is based on our discoveries that the C. elegans protein, TCER-1, acts as a metabolic switch that regulates lipid hydrolysis to shape the energetic trade-off be- tween immunity and fertility. We identified TCER-1, homolog of human transcription elongation/splicing factor, TCERG1, as a protein that promoted longevity specifically in response to reproductive signals, by establishing lipid homeostasis. TCER-1 is critical for reproductive fitness. Recently, we reported that TCER-1 represses immunity exclusively during the fertile stages of life; raising its level alleviates infection-induced fertility decline, suggesting that it may inhib- it immunity to promote reproductive fitness. In unpublished, preliminary studies, we have now discovered that TCER-1 is critical for proper fat deposition into eggs. Additionally, through an unbiased RNA-Seq analysis, we found that TCER-1 controls the alternative splicing (AS) and differential expression of multiple diglyceride (DAG) and triglyceride (TAG) lipases, respectively, both during normal reproduction and upon infection. Hence, we hypothesize that TCER-1 widely alters lipid hydrolysis, through regulation of lipase expression and alterna- tive splicing, to repress immunity and support fertility. We propose to test this hypothesis by exploring the mechanisms by which the DAG- and TAG-lipases regulated by TCER-1 impact immunity and maternal-fetal li- pid distribution. We will also investigate how TCER-1 dictates the maternal and embryonic lipidomes during normal conditions and upon pathogen exposure. Overall, this study will reveal fundamental mechanisms by which fat allocation towards distinct physiological purposes is determined. Further significant advances that may be achieved through this work include demonstration of (i) a central role for fat hydrolysis in maternal-fetal lipid distribution, and (ii) splicing as a key regulatory step in shaping host-pathogen combat.