Abstract
Ribonuclease L (RNase-L) is an endoribonuclease well known for its roles in innate immunity. Recently it has been shown to regulate several cellular functions by modulating the levels of specific mRNAs. In this study, we investigated whether RNase-L may regulate adipocyte functions. We showed that knockdown of RNase-L reduced 3T3-L1 adipocyte differentiation and lipid accumulation. After mRNA profiling, we found that upregulation of Pref-1 mRNA, an inhibitory regulator of adipogenesis, could explain the reduced adipocyte differentiation with RNase-L downregulation. The signaling molecules downstream to Pref-1, including focal adhesion kinase, extracellular signal-regulated kinases and SRY-box 9, were activated by RNase-L suppression. The presence of Pref-1 mRNA was detected in the mRNP complexes precipitated by anti-RNase-L antibody. Moreover, the Pref-1 mRNA decay rate was raised by elevated RNase-L ribonuclease activity. Finally, in stable cell clones with RNase-L silencing, suppression of Pref-1 mRNA by specific siRNA partially recovered the adipocyte differentiation phenotype. Consistent with our findings, meta-analysis of 45 public array datasets from seven independent studies showed a significant negative relationship between RNase-L and Pref-1 mRNA levels in mouse adipose tissues. Higher RNase-L and lower Pref-1 mRNAs were found in the adipose tissues of high-fat diet mice compared to those of ND mice. In line with this, our animal data also showed that the adipose tissues of obese rats contained higher RNase-L and lower Pref-1 expression in comparison to that of lean rats. This study demonstrated that Pref-1 mRNA is a novel substrate of RNase-L. RNase-L is involved in adipocyte differentiation through destabilizing Pref-1 mRNA, thus offering a new link among RNA metabolism, innate immunity and adipogenesis in obesity progression.
Highlights
Ribonuclease L (RNase-L) is an innate immune mediator in mammalian cells
In order to investigate whether RNase-L plays a role in adipocyte differentiation, we first analyzed the changes of RNase-L expression during 3T3-L1 differentiation by qPCR
We reported that the adipocyte differentiation of 3T3-L1 was reduced by RNase-L knockdown and this inverse relation between RNase-L and pre-adipocyte factor-1 (Pref-1) in adipogenesis is observed in obesity progression in animals (Figure 8)
Summary
Ribonuclease L (RNase-L) is an innate immune mediator in mammalian cells It participates in antiviral and antibacterial activities induced by type I interferon through the activation of oligoadenylate synthetase (OAS)-RNase-L-retinoic acidinducible gene 1 pathway.[1] Taking its antiviral action as an example, once the invading viral RNAs are recognized, OAS is activated to produce 2-5A (ppp5′A[2′p5′A]n). The activated RNase-L recognizes and degrades the viral RNAs to hinder further viral replication and to promote a series of downstream signals, which turn on the inflammatory responses, such as interferonα, interferonβ, interleukin-1β and tumor necrosis factor-α production.[2,3,4] In addition to its roles in the defense against microorganisms, RNase-L, through these inflammatory responses, was reported to be involved in the progression of islet inflammation in a type 1 diabetes mellitus animal model.[5] The association between the mutations of human. Obesity is not a state of excessive fat accumulation, but is considered as a condition with chronic low-grade inflammation, coined as metainflammation.[14,15] Since RNase-L has a classical role in innate immunity and has adopted some new identities as regulators of other cellular functions, we are interested in whether it may modulate adipocyte functions
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