| First Author | Zhao J | Year | 2019 |
| Journal | Cell Cycle | Volume | 18 |
| Issue | 23 | Pages | 3378-3392 |
| PubMed ID | 31595820 | Mgi Jnum | J:296477 |
| Mgi Id | MGI:6467850 | Doi | 10.1080/15384101.2019.1677074 |
| Citation | Zhao J, et al. (2019) Retinoic acid inducible gene-I slows down cellular senescence through negatively regulating the integrin beta3/p38 MAPK pathway. Cell Cycle 18(23):3378-3392 |
| abstractText | 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, Rig-I(-/-) 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 beta3 was negatively regulated by Rig-I, and significantly upregulated with the occurrence of senescence. Gene silencing of Itgb3 (encoding integrin beta3) retarded the progression of cellular senescence in both WT and Rig-I(-/-) MEFs. Notably, this effect was more prominent in Rig-I(-/-) MEFs. Furthermore, p38 MAPK was a key downstream molecule for integrin beta3-mediated senescence, and overactivated in senescent Rig-I(-/-) MEFs. Taken together, Rig-I deficiency contributes to cellular senescence through amplifying integrin beta3/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.Abbreviations: 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-1beta: 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-beta-gal: senescence-associated beta-galactosidase; qPCR: quantitative reverse-transcription PCR; PBS: phosphate-buffered saline. |
