Retinoic acid inducible gene-I slows down cellular senescence through negatively regulating the integrin β3/p38 MAPK pathway.

Retinoic acid inducible gene-I (Rig-I) has been well documented as a cytosolic pattern recognition receptor that can sense viral RNA ligands to initiate the interferon-mediated antiviral immunity. However, little is known about the biological behaviors of Rig-I devoid of viral infection. Herein, we investigated the roles of Rig-I in the regulation of cellular senescence. In comparison to wild-type counterparts, mice displayed the accelerated loss of hair, less responsiveness to gentle physical stimuli and shorten survival time. Likewise, Rig-I deficiency rendered mouse embryonic fibroblasts (MEFs) more susceptible to the serial passages-associated replicative senescence. By performing a transcriptome analysis, we identified integrins at the intersections of biological pathways affected by Rig-I. Among these, integrin β3 was negatively regulated by Rig-I, and significantly upregulated with the occurrence of senescence. Gene silencing of Itgb3 (encoding integrin β3) retarded the progression of cellular senescence in both WT and MEFs. Notably, this effect was more prominent in MEFs. Furthermore, p38 MAPK was a key downstream molecule for integrin β3-mediated senescence, and overactivated in senescent MEFs. Taken together, Rig-I deficiency contributes to cellular senescence through amplifying integrin β3/p38 MAPK signaling. Our findings provide the evidence that Rig-I is a key regulator of cellular senescence, which will be helpful in better understanding its function without viral infection. Rig-I: retinoic acid inducible gene-I; SASP: senescence-associated secretory phenotype; ECM: extracellular matrix; Itgb3: integrin beta 3; PRR: pattern recognition receptor; MEFs: mouse embryonic fibroblasts; Il-1β: interleukin-1 beta; Il-6: interleukin-6; Il-8: interleukin-8; Cxcl1: chemokine (C-X-C motif) ligand 1; Ccl2: chemokine (C-C motif) ligand 2; WT, wild type; BM: bone marrow; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinases; JNK: Jun N-terminal kinases; SA-β-gal: senescence-associated β-galactosidase; qPCR: quantitative reverse-transcription PCR; PBS: phosphate-buffered saline.