Institute for Biomedical Aging Research, University of Innsbruck, Rennweg 10, 6020, Innsbruck, Austria.
Department of Hematology, Oncology and Immunology, Philipps-University Marburg, and University Hospital Giessen and Marburg, Baldingerstrasse, 35032, Marburg, Germany.
BMC Genomics. 2022 Jan 4;23(1):25. doi: 10.1186/s12864-021-08176-y.
In the nematode Caenorhabditis elegans, longevity in response to germline ablation, but not in response to reduced insulin/IGF1-like signaling, is strongly dependent on the conserved protein kinase minibrain-related kinase 1 (MBK-1). In humans, the MBK-1 ortholog DYRK1A is associated with a variety of disorders, most prominently with neurological defects observed in Down syndrome. To better understand mbk-1's physiological roles and their dependence on genetic background, we analyzed the influence of mbk-1 loss on the transcriptomes of wildtype and long-lived, germline-deficient or insulin-receptor defective, C. elegans strains by RNA-sequencing.
mbk-1 loss elicited global changes in transcription that were less pronounced in insulin-receptor mutant than in germline-deficient or wildtype C. elegans. Irrespective of genetic background, mbk-1 regulated genes were enriched for functions in biological processes related to organic acid metabolism and pathogen defense. qPCR-studies confirmed mbk-1 dependent induction of all three C. elegans Δ9-fatty acid desaturases, fat-5, fat-6 and fat-7, in wildtype, germline-deficient and insulin-receptor mutant strains. Conversely, mbk-1 dependent expression patterns of selected pathogen resistance genes, including asp-12, dod-24 and drd-50, differed across the genetic backgrounds examined. Finally, cth-1 and cysl-2, two genes which connect pathogen resistance to the metabolism of the gaseous messenger and lifespan regulator hydrogen sulfide (HS), were commonly suppressed by mbk-1 loss only in wildtype and germline-deficient, but not in insulin-receptor mutant C. elegans.
Our work reveals previously unknown roles of C. elegans mbk-1 in the regulation of fatty acid desaturase- and HS metabolic-genes. These roles are only partially dependent on genetic background. Considering the particular importance of fatty acid desaturation and HS for longevity of germline-deficient C. elegans, we propose that these processes at least in part account for the previous observation that mbk-1 preferentially regulates lifespan in these worms.
在秀丽隐杆线虫中，生殖系消融引起的寿命延长，但不是胰岛素/IGF1 样信号减少引起的寿命延长，强烈依赖于保守的蛋白激酶 minibrain-related kinase 1（MBK-1）。在人类中，MBK-1 同源物 DYRK1A 与多种疾病有关，最突出的是唐氏综合征中观察到的神经缺陷。为了更好地了解 mbk-1 的生理作用及其对遗传背景的依赖性，我们通过 RNA-seq 分析了 mbk-1 缺失对野生型和长寿、生殖系缺失或胰岛素受体缺陷的秀丽隐杆线虫菌株转录组的影响。
mbk-1 缺失引起了转录的全局变化，这些变化在胰岛素受体突变体中比在生殖系缺失或野生型秀丽隐杆线虫中不那么明显。无论遗传背景如何，mbk-1 调节的基因富集了与有机酸代谢和病原体防御相关的生物学过程的功能。qPCR 研究证实，mbk-1 在野生型、生殖系缺失和胰岛素受体突变体菌株中都能诱导所有三种秀丽隐杆线虫 Δ9-脂肪酸去饱和酶 fat-5、fat-6 和 fat-7 的表达。相反，mbk-1 依赖的选定病原体抗性基因的表达模式，包括 asp-12、dod-24 和 drd-50，在研究的遗传背景中有所不同。最后，cth-1 和 cysl-2，这两个将病原体抗性与气态信使和寿命调节剂硫化氢（HS）代谢联系起来的基因，仅在野生型和生殖系缺失的秀丽隐杆线虫中，而不是在胰岛素受体突变体中，被 mbk-1 缺失共同抑制。
我们的工作揭示了秀丽隐杆线虫 mbk-1 在调节脂肪酸去饱和酶和 HS 代谢基因方面的先前未知作用。这些作用在一定程度上依赖于遗传背景。考虑到生殖系缺失的秀丽隐杆线虫中脂肪酸去饱和和 HS 对寿命的特别重要性，我们提出这些过程至少部分解释了之前观察到的 mbk-1 优先调节这些线虫寿命的现象。
