The long noncoding RNA GUARDIN functions to protect genome stability. Inhibiting GUARDIN expression can alter cell fate decisions toward senescence or apoptosis, but the underlying molecular signals are unknown. Here, we show that GUARDIN is an essential component of a transcriptional repressor complex involving LRP130 and PGC1α. GUARDIN acts as a scaffold to stabilize LRP130/PGC1α heterodimers and their occupancy at the FOXO4 promotor. Destabilizing this complex by silencing of GUARDIN, LRP130, or PGC1α leads to increased expression of FOXO4 and upregulation of its target gene p21, thereby driving cells into senescence. We also found that GUARDIN expression was induced by rapamycin, an agent that suppresses cell senescence. FOS-like antigen 2 (FOSL2) acts as a transcriptional repressor of GUARDIN, and lower FOSL2 levels in response to rapamycin correlate with increased levels of GUARDIN. Together, these results demonstrate that GUARDIN inhibits p21-dependent senescence through a LRP130-PGC1α-FOXO4 signaling axis, and moreover, GUARDIN contributes to the anti-aging activities of rapamycin.

中文翻译：

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LncRNA GUARDIN 通过依赖 LRP130-PGC1α-FOXO4-p21 的信号轴抑制细胞衰老。

长链非编码 RNA GUARDIN 起到保护基因组稳定性的作用。抑制 GUARDIN 表达可以改变细胞命运对衰老或凋亡的决定，但潜在的分子信号尚不清楚。在这里，我们表明 GUARDIN 是涉及 LRP130 和 PGC1α 的转录抑制复合物的重要组成部分。GUARDIN 作为支架来稳定 LRP130/PGC1α 异二聚体及其在 FOXO4 启动子上的占有率。通过沉默 GUARDIN、LRP130 或 PGC1α 来破坏这种复合物的稳定性会导致 FOXO4 的表达增加和其靶基因 p21 的上调，从而驱动细胞衰老。我们还发现 GUARDIN 表达是由雷帕霉素诱导的，雷帕霉素是一种抑制细胞衰老的药物。FOS 样抗原 2 (FOSL2) 充当 GUARDIN 的转录抑制因子，响应雷帕霉素的较低 FOSL2 水平与增加的 GUARDIN 水平相关。总之，这些结果表明，GUARDIN 通过 LRP130-PGC1α-FOXO4 信号轴抑制 p21 依赖性衰老，此外，GUARDIN 有助于雷帕霉素的抗衰老活性。