RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis
Apoptosis of virus-infected cells is an effective antiviral mechanism in addition to interferon induction to establish antiviral state to restrict virus spread. The interferon-inducible 2′−5′ oligoadenylate synthetase/RNase L pathway results in activation of RNase L in...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/20/14/3535 |
| _version_ | 1811198092040470528 |
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| author | Praveen Manivannan Vidita Reddy Sushovita Mukherjee Kirsten Neytania Clark Krishnamurthy Malathi |
| author_facet | Praveen Manivannan Vidita Reddy Sushovita Mukherjee Kirsten Neytania Clark Krishnamurthy Malathi |
| author_sort | Praveen Manivannan |
| collection | DOAJ |
| description | Apoptosis of virus-infected cells is an effective antiviral mechanism in addition to interferon induction to establish antiviral state to restrict virus spread. The interferon-inducible 2′−5′ oligoadenylate synthetase/RNase L pathway results in activation of RNase L in response to double stranded RNA and cleaves diverse RNA substrates to amplify interferon induction and promote apoptosis. Here we show that RNase L induces expression of Death-associated protein kinase-Related Apoptosis-inducing protein Kinase 1 (DRAK1), a member of the death-associated protein kinase family and interferon-signaling pathway is required for induction. Overexpression of DRAK1 triggers apoptosis in the absence of RNase L activation by activating c-Jun N-terminal kinase (JNK), translocation of BCL2 Associated X (Bax) to the mitochondria accompanied by cytochrome C release and loss of mitochondrial membrane potential promoting cleavage of caspase 3 and Poly(ADP-Ribose) Polymerase 1 (PARP). Inhibitors of JNK and caspase 3 promote survival of DRAK1 overexpressing cells demonstrating an important role of JNK signaling pathway in DRAK1-mediated apoptosis. DRAK1 mutant proteins that lack kinase activity or nuclear localization fail to induce apoptosis highlighting the importance of cellular localization and kinase function in promoting cell death. Our studies identify DRAK1 as a mediator of RNase L-induced apoptosis. |
| first_indexed | 2024-04-12T01:24:59Z |
| format | Article |
| id | doaj.art-133e829e98684c8896331397dd3e3164 |
| institution | Directory Open Access Journal |
| issn | 1422-0067 |
| language | English |
| last_indexed | 2024-04-12T01:24:59Z |
| publishDate | 2019-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-133e829e98684c8896331397dd3e31642022-12-22T03:53:40ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-07-012014353510.3390/ijms20143535ijms20143535RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote ApoptosisPraveen Manivannan0Vidita Reddy1Sushovita Mukherjee2Kirsten Neytania Clark3Krishnamurthy Malathi4Department of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606, USADepartment of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606, USADepartment of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606, USADepartment of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606, USADepartment of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606, USAApoptosis of virus-infected cells is an effective antiviral mechanism in addition to interferon induction to establish antiviral state to restrict virus spread. The interferon-inducible 2′−5′ oligoadenylate synthetase/RNase L pathway results in activation of RNase L in response to double stranded RNA and cleaves diverse RNA substrates to amplify interferon induction and promote apoptosis. Here we show that RNase L induces expression of Death-associated protein kinase-Related Apoptosis-inducing protein Kinase 1 (DRAK1), a member of the death-associated protein kinase family and interferon-signaling pathway is required for induction. Overexpression of DRAK1 triggers apoptosis in the absence of RNase L activation by activating c-Jun N-terminal kinase (JNK), translocation of BCL2 Associated X (Bax) to the mitochondria accompanied by cytochrome C release and loss of mitochondrial membrane potential promoting cleavage of caspase 3 and Poly(ADP-Ribose) Polymerase 1 (PARP). Inhibitors of JNK and caspase 3 promote survival of DRAK1 overexpressing cells demonstrating an important role of JNK signaling pathway in DRAK1-mediated apoptosis. DRAK1 mutant proteins that lack kinase activity or nuclear localization fail to induce apoptosis highlighting the importance of cellular localization and kinase function in promoting cell death. Our studies identify DRAK1 as a mediator of RNase L-induced apoptosis.https://www.mdpi.com/1422-0067/20/14/3535RNase LDRAK1apoptosisinterferon signalingJNK |
| spellingShingle | Praveen Manivannan Vidita Reddy Sushovita Mukherjee Kirsten Neytania Clark Krishnamurthy Malathi RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis International Journal of Molecular Sciences RNase L DRAK1 apoptosis interferon signaling JNK |
| title | RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis |
| title_full | RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis |
| title_fullStr | RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis |
| title_full_unstemmed | RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis |
| title_short | RNase L Induces Expression of A Novel Serine/Threonine Protein Kinase, DRAK1, to Promote Apoptosis |
| title_sort | rnase l induces expression of a novel serine threonine protein kinase drak1 to promote apoptosis |
| topic | RNase L DRAK1 apoptosis interferon signaling JNK |
| url | https://www.mdpi.com/1422-0067/20/14/3535 |
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