LncRNA GUARDIN suppresses cellular senescence through a LRP130-PGC1α-FOXO4-p21-dependent signaling axis

Abstract

The long non-coding RNA GUARDIN functions to protect genome stability. Inhibiting GUARDIN expression can alter cell fate decisions towards 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 PGC1 which suppresses FOXO4 expression. GUARDIN acts as a scaffold to stabilize LRP130/PGC1 heterodimers and their occupancy at the FOXO4 promotor. Destabilizing this complex by silencing of GUARDIN, LRP130 or PGC1 leads to FOXO4-dependent upregulation of p21, thereby driving cells into senescence. We also found that GUARDIN expression was induced by rapamycin, a senolytic agent that suppresses cell senescence. FOS-Like Antigen 2 (FOSL2) acts as a transcriptional repressor of GUARDIN with increased levels in the presence of rapamycin resulting from downregulation of FOSL2. Together, these results demonstrate that GUARDIN inhibits p21-dependent senescence through a LRP130-PGC1-FOXO4 signaling axis and moreover, GUARDIN contributes to the anti-senolytic activities of rapamycin.