Endoribonuclease L (RNase L) Regulates the Myogenic and Adipogenic Potential of Myogenic Cells

Skeletal muscle maintenance and repair involve several finely coordinated steps in which pluripotent stem cells are activated, proliferate, exit the cell cycle and differentiate. This process is accompanied by activation of hundreds of muscle-specific genes and repression of genes associated with cell proliferation or pluripotency. Mechanisms controlling myogenesis are precisely coordinated and regulated in time to allow the sequence of activation/inactivation of genes expression. Muscular differentiation is the result of the interplay between several processes such as transcriptional induction, transcriptional repression and mRNA stability. mRNA stability is now recognized as an essential mechanism of control of gene expression. For instance, we previously showed that the endoribonuclease L (RNase L) and its inhibitor (RLI) regulates MyoD mRNA stability and consequently muscle differentiation

[RNase L, a crucial mediator of innate immunity and other cell functions.]

5 pagesInternational audienceThe 2-5A/RNase L pathway is one of the first cellular defences against viruses. RNase L is an unusual endoribonuclease which activity is strictly regulated by its binding to a small oligonucleotide, 2-5A. 2-5A itself is very unusual, consisting of a series of 5'- triphosphorylated oligoadenylates with 2'-5' bonds. But RNase L activity is not limited to viral RNA cleavage. RNase L plays a central role in innate immunity, apoptosis, cell growth and differentiation by regulating cellular RNA stability and expression. Default in its activity leads to increased susceptibility to virus infections and to tumor development. RNase L gene has been identified as HPC1 (Hereditary Prostate Cancer 1) gene. Study of RNase L variant R462Q in etiology of prostate cancer has led to the identification of the novel human retrovirus closely related to xenotropic murine leukemia viruses (MuLVs) and named XMRV

La RNase L, un acteur essentiel de la réponse cellulaire antivirale

La RNase L, une endoribonuclease activée lors d’une infection virale, est l’effecteur enzymatique d’une voie de dégradation des ARN simple brin. Son activité n’est pas limitée à la dégradation des ARN viraux. Elle joue un rôle majeur dans l’immunité innée, l’apoptose et la différenciation en régulant aussi l’expression et la stabilité d’ARN cellulaires. La dérégulation de son activité est impliquée dans la susceptibilité à l’infection virale et le développement tumoral. Le gène RNase L a été identifié comme HPC1 (hereditary prostate cancer 1), l’un des gènes de susceptibilité au cancer de la prostate. L’étude de son rôle dans ce cancer a permis l’identification d’un nouveau rétrovirus humain, le xenotropic murine leukaemia related virus (XMRV) qui est un virus proche des rétrovirus leucémiques murins (MuLV)

Localization of the Ribonuclease L Inhibitor Gene (RNS4I), a New Member of the Interferon-Regulated 2–5A Pathway, to 4q31 by Fluorescencein SituHybridization

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Cloning and Characterization of a RNase L Inhibitor.

International audienceThe 2-5A/RNase L system is considered as a central pathway of interferon (IFN) action and could possibly play a more general physiological role as for instance in the regulation of RNA stability in mammalian cells.We describe here the expression cloning and initial characterization of RLI (for RNase L inhibitor), a new type of endoribonuclease inhibitor.RLI cDNA codes for a 68-kDa polypeptide whose expression is not regulated by IFN. Its expression in reticulocyte extracts antagonizes the 2-5A binding ability and the nuclease activity of endogenous RNase L or the cloned 2DR polypeptide. The inhibition requires the association of RLI with the nuclease and is dependent on the ratio between the two proteins. Likewise RLI is co-immunoprecipitated with the RNase L complex by a nuclease-specific antibody. RLI does not lead to 2-5A degradation or to irreversible modification of RNase L. The overexpression of RLI in stably transfected HeLa cells inhibits the antiviral activity of IFN on encephalomyocarditis virus but not on vesicular stomatitis virus.RLI therefore appears as the first described and potentially important mediator of the 2-5A/RNase L pathway

RNase L Inhibitor Is Induced during Human Immunodeficiency Virus Type 1 Infection and Down Regulates the 2-5A/RNase L Pathway in Human T Cells

The interferon-regulated 2-5A/RNase L pathway plays a major role in the antiviral and antiproliferative activities of these cytokines. Several viruses, however, have evolved strategies to escape the antiviral activity of the 2-5A/RNase L pathway. In this context, we have cloned a cDNA coding for the RNase L inhibitor (RLI), a protein that specifically inhibits RNase L and whose regulated expression in picornavirus-infected cells down regulates the activity of the 2-5A/RNase L pathway. We show here that RLI increases during the course of human immunodeficiency virus type 1 (HIV-1) infection, which may be related to the downregulation of RNase L activity that has been described to occur in HIV-infected cells. In order to establish a possible causal relationship between these observations, we have stably transfected H9 cells with RLI sense or antisense cDNA-expressing vectors. The overexpression of RLI causes a decrease in RNase L activity and a twofold enhancement of HIV production. This increase in HIV replication correlates with an increase in HIV RNA and proteins. In contrast, reduction of RLI levels in RLI antisense cDNA-expressing clones reverses the inhibition of RNase L activity associated with HIV multiplication and leads to a threefold decrease in the viral load. This anti-HIV activity correlated with a decrease in HIV RNA and proteins. These findings demonstrate that the level of RLI, via its modulation of RNase L activity, can severely impair HIV replication and suggest the involvement of RLI in the inhibition of the 2-5A/RNase L system observed during HIV infection

The 2–5A/RNase L/RNase L Inhibitor (RNI) Pathway Regulates Mitochondrial mRNAs Stability in Interferon α-treated H9 Cells

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The 2-5A/RNase L Pathway and Inhibition by RNase L Inhibitor (RLI)

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Decreased RNF41 expression leads to insulin resistance in skeletal muscle of obese women

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