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The Role of Mixed Lineage Kinase 3 in MAVS- Dependent Signaling

Stefl, Samantha Jean
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1438955382

Abstract Details

2015, Master of Science, University of Toledo, Biology (Cell-Molecular Biology).
The innate immune system is the first line of defense against infection. Specific pathways are activated by detection of pathogen-specific molecules that are distinct from host antigens. The RIG- like helicase (RLH) pathway includes the cytoplasmic pattern recognition receptors RIG-I and MDA-5, two related RNA helicases that recognize and bind cytoplasmic dsRNA and ssRNA of viral origin. Once activated, RIG-I and MDA5 associate with the mitochondrial antiviral signaling adaptor protein (MAVS), leading to activation of downstream transcription factors NF-¿B and IFN regulatory factors (IRFs) such as IRF3. These transcription factors translocate to the nucleus where they induce expression of type I IFNs, including IFNß, and other pro-inflammatory genes. The MAPK pathway has also been implicated in virus detection and response. Environmental stimuli such as inflammatory cytokines trigger the MAPK pathway. MAP3Ks including Mixed lineage kinase 3 (MLK3) phosphorylate and activate MAP2Ks, which then phosphorylate and activate MAPKs such as p38, JNK and ERK. The MAPKs then activate transcription factors that regulate expression of genes involved in cell proliferation, differentiation and apoptosis. The current understanding of MLK3 is limited. Within the MAPK system, MLK3 has been implicated as a regulator of signaling pathways JNK, ERK and p38. MLK3 is activated by various cellular stressors or through TNF¿¿¿stimulated recruitment of TRAF2. MAPK pathways assist in virus detection as shown by the MAVS recruitment of MKK4/7 and the presence of TRAF2 and other adaptor proteins in the RLH activated pathways. Our data suggest that MLK3 overexpression negatively regulates MDA5 and/or MAVS-dependent signaling and suppresses IFN¿ promoter activation. Suppression of endogenous MLK3 using siRNA upregulated IFNß¿gene induction by dsRNA. The negative regulatory role of MLK3 on IFNß production is dependent on its kinase activity. TRAF2-MLK3 association is observed in unstimulated SKOV3 cells. We have also observed an inhibitory effect of MLK3 on IRF3 activation in cells with transient MAVS or TRAF2 overexpression. Collectively our results suggest MLK3 is a regulator of IFNß signaling downstream of RLH signaling.
Douglas Leaman , Dr. (Committee Chair)
Deborah Chadee, Dr. (Committee Member)
Malathi Krishnamurthy, Dr. (Committee Member)
Travis Taylor , Dr. (Committee Member)
61 p.
Biology; Cellular Biology; Molecular Biology

Recommended Citations

Citations

  • Stefl, S. J. (2015). The Role of Mixed Lineage Kinase 3 in MAVS- Dependent Signaling [Master's thesis, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1438955382

    APA Style (7th edition)

  • Stefl, Samantha. The Role of Mixed Lineage Kinase 3 in MAVS- Dependent Signaling . 2015. University of Toledo, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1438955382.

    MLA Style (8th edition)

  • Stefl, Samantha. "The Role of Mixed Lineage Kinase 3 in MAVS- Dependent Signaling ." Master's thesis, University of Toledo, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1438955382

    Chicago Manual of Style (17th edition)

toledo1438955382
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© 2015, all rights reserved.
This open access ETD is published by University of Toledo and OhioLINK.