Interferon action and apoptosis are defective in mice devoid of 2',5'-oligoadenylate-dependent RNase L

Zhou, Aimin; Paranjape, Jayashree M.; Brown, Thomas L.; Nie, Huiqin; Naik, Sharon; Dong, Bin; Chang, Ansi; Trapp, Bruce D.; Fairchild, Robert L.; Colmenares, Clemencia; Silverman, Robert H.

doi:10.1093/emboj/16.21.6355

Cited by 515 publications

(459 citation statements)

References 47 publications

Supporting

Mentioning

446

Contrasting

Unclassified

Order By: Relevance

“…However, we and others have shown that activation of RNase L beyond an ill-defined threshold causes apoptosis [69,[79][80][81][82][83]. Therefore, activation of RNase L could lead to elimination of virus-infected cells under some circumstances.…”

Section: Involvement Of Rnase L In the Antiviral Action Of Ifnsmentioning

confidence: 91%

“…By using radioactively labeled 2-5A, we showed that mice expressed RNase L in every tissue type that was analyzed [69]. In addition, RNase L pre-exists in a wide range of different human cell types and tissues due to the presence of several different tissue specific promoter elements in the RNASEL gene [84].…”

Section: Nih Public Accessmentioning

confidence: 98%

“…In addition, RNase L pre-exists in a wide range of different human cell types and tissues due to the presence of several different tissue specific promoter elements in the RNASEL gene [84]. In contrast, no 2-5A binding proteins were detected in several different organs of Rnasel −/− mice [69]. Therefore, the ability to bind 2-5A with high affinity (K D = 40 pM) [85] is a unique biochemical property of RNase L. As a result, 2-5A is an unambiguous signal for initiating RNA cleavage through activation of RNase L.…”

Section: Involvement Of Rnase L In the Antiviral Action Of Ifnsmentioning

confidence: 99%

Section: Involvement Of Rnase L In the Antiviral Action Of Ifnsmentioning

confidence: 99%

“…To address this question, we generated RNase L gene knockout mice [69]. The RNase L-deficient mice which have enhanced susceptibility to infections by the picornaviruses, EMCV or Coxsackievirus B4 [69,70], herpes simplex virus 1 (HSV-1) [71], and the flavivirus, West Nile virus [72]. Interestingly, there are presently a few instances in which RNase L actually promotes viral diseases and/or replication, rather than blocking it [73,74].…”

Section: Involvement Of Rnase L In the Antiviral Action Of Ifnsmentioning

confidence: 99%

See 4 more Smart Citations

A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

View full text Add to dashboard Cite

The antiviral and antitumor actions of interferons are caused, in part, by a remarkable regulated RNA cleavage pathway known as the 2-5A/RNase L system. 2′-5′ linked oligoadenylates (2-5A) are produced from ATP by interferon-inducible synthetases. 2-5A activates pre-existing RNase L, resulting in the cleavage of RNAs within single-stranded regions. Activation of RNase L by 2-5A leads to an antiviral response, although precisely how this happens is a subject of ongoing investigations. Recently, RNase L was identified as the hereditary prostate cancer 1 gene. That finding has led to the discovery of a novel human retrovirus, XMRV. My scientific journey through the 2-5A system recounts some of the highlights of these efforts. Knowledge gained from studies on the 2-5A system could have an impact on development of therapies for important viral pathogens and cancer.Keywords 2-5A; RNase L; interferon; cancer; virus Background on the 2-5A/RNase L systemOver the past thirty-years, investigations into the mechanisms of interferon (IFN) action have elucidated how antiviral innate immunity operates within and between mammalian cells. The focus of my work over this period has been, and continues to be, probing the biology and biochemistry of the 2-5A/RNase L system, and studying its roles in health and disease. My scientific journey, from basic research to clinical studies, are summarized in this monograph. The 2-5A/RNase L system is one the principal pathways by which IFNs suppress viral infections. Exposure of cells to IFNs induces expression of genes that result in an "antiviral state". Type I IFNs bind to the IFN-α receptor 1 (IFNAR1) and IFNAR2 polypeptide chains on cell surfaces initiating JAK-STAT signaling to the IFN stimulated genes (ISGs) [1]. Included among over a hundred different ISGs are genes encoding 2-5A synthetases (OAS) [2,3]. The OAS genes are a family of ISGs that function in the 2-5A/RNase L system (Fig. 1). In humans there are three functional OAS genes (OAS1-3), resulting in 8 to 10 OAS isoforms due to alternative mRNA splicing [4]. In mice, in addition to OAS2 and OAS3 there are 7 separate OAS1 genes, including OAS1b, the flavivirus resistance gene (Flv r ] [5][6][7][8]. When stimulated by dsRNA, the functional OAS proteins produce a series of short 5′-phosphorylated, 2′,5′-linked oligoadenylates collectively referred to as 2-5A [p x 5′A(2′p5′A) n ; x = 1-3; n≥2] from ATP [9]. The first molecular clone for an OAS was obtained by Michel Revel's lab [10]. Biochemical characterization of OAS proteins by Ara Hovanessian's lab [11][12][13][14] and Ganes Sen's lab [15][16][17][18][19] and a crystal structure by Rune Hartmann and Vivien Yee (in collaboration with Ganes Sen and Just Justesen) [20] have led to functional and structural insight into the OAS family of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, type...

show abstract

Section: Involvement Of Rnase L In the Antiviral Action Of Ifnsmentioning

confidence: 91%

Section: Nih Public Accessmentioning

confidence: 98%

Section: Involvement Of Rnase L In the Antiviral Action Of Ifnsmentioning

confidence: 99%

Section: Involvement Of Rnase L In the Antiviral Action Of Ifnsmentioning

confidence: 99%

Section: Involvement Of Rnase L In the Antiviral Action Of Ifnsmentioning

confidence: 99%

See 3 more Smart Citations

A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

View full text Add to dashboard Cite

show abstract

Involvement of Fas/Fas ligand system-mediated apoptosis in the development of concanavalin A-induced hepatitis

1998

View full text Add to dashboard Cite

Concanavalin A (Con A)-induced hepatitis is an experimental hepatitis model in which hepatic injury is caused by the action of cytokines produced by T cells. Using IFN-gamma-deficient mice, we previously demonstrated that IFN-gamma plays a central role in Con A-induced hepatitis. Here, we show that development of the disease is completely suppressed in gld/gld mice, in which Fas ligand is defective. In contrast, suppression of the disease in Ipr/Ipr mice was incomplete, since a small amount of the fas mRNA was produced in these mice. The data indicate that activation of the Fas/Fas ligand system is a necessary step in the development of Con A-induced hepatitis. Furthermore, we found that not only fas but also caspase-1 expression was reduced in IFN-gamma-deficient mice. Since caspase-1 is an integral component of Fas signal transduction, these observations suggest that IFN-gamma-induced activation of both fas and caspase-1 expression causes enhancement of hepatocyte apoptosis resulting in the development of hepatitis.

show abstract

RibonucleaseL

Silverman

2002

Wiley Encyclopedia of Molecular Medicine

View full text Add to dashboard Cite

Interferon action and apoptosis are defective in mice devoid of 2',5'-oligoadenylate-dependent RNase L

Cited by 515 publications

References 47 publications

A scientific journey through the 2-5A/RNase L system

A scientific journey through the 2-5A/RNase L system

Involvement of Fas/Fas ligand system-mediated apoptosis in the development of concanavalin A-induced hepatitis

RibonucleaseL

Contact Info

Product

Resources

About