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Kelly Arcipowski


Mentor: Gail Bishop, Ph.D.
Lab Room: 2219 MERF
Lab Phone: 319-335-7816

Molecular mechanisms of TRAF6 utilization by the oncogenic viral mimic of CD40, LMP1

Latent membrane protein 1 (LMP1), encoded by Epstein-Barr virus (EBV), is required for EBV-mediated B cell transformation. LMP1 is a constitutively active functional mimic of the tumor-necrosis factor receptor (TNFR) superfamily member CD40, utilizing TNFR-associated factor (TRAF) adaptor proteins to induce signaling; however, LMP1 requires TRAF3 for signaling, while TRAF3 is a negative regulator of CD40 signaling. Furthermore, LMP1 signals are amplified and sustained compared to CD40 signals. Previous work shows that although both CD40 and LMP1 require TRAF6 to activate the JNK pathway, CD40 interacts with TRAF6 directly while TRAF6 interaction with LMP1 has not yet been demonstrated. Similarly, Toll-like receptors (TLRs) appear to use TRAF6 to mediate downstream signaling without binding TRAF6 directly. We wish to investigate how LMP1 uses TRAF6 to mediate signaling. Our central hypothesis is that TRAF6 is used by LMP1 in two ways: LMP1 uses TRAF6 through direct association (like CD40) and in an indirect manner (like TLRs).We have found that TRAF6 is required for LMP1 functions and that, unlike CD40, LMP1 requires the presence of the TRAF6 TRAF-C receptor-binding domain for activation of signaling pathways. In addition, we found that TRAF6 associates with the TRAF1/2/3/5 binding site on LMP1, which was surprising because TRAF6 associates with CD40 at a site that is distinct from that shared by the other TRAFs. Our recent experiments show evidence for a direct association of TAK1 with TRAF6 in mouse B cells stimulated via a receptor with the LMP1 cytoplasmic tail, previously shown by our lab to be necessary and sufficient for LMP1-mediated activation signals. Furthermore, phosphorylation of TAK1 appears to be significant in LMP1-mediated, TRAF6-dependent signaling. Current studies further explore the molecular mechanisms of TRAF6 and TAK1 utilization by LMP1, including the role of these proteins in LMP1 functions in vivo. Information gained from these studies will be important for future design of TRAF-targeted therapies to block or reverse LMP1’s pathogenic effects.

Publications:

Arcipowski KM, Bishop GA. Roles of the Kinase TAK1 in TRAF6-Dependent Signaling by CD40 and Its Oncogenic Viral Mimic, LMP1. PLoS One. 2012;7(7):e42478. Epub 2012 Jul 30. PubMed PMID: 22860133; PubMed Central PMCID: PMC3408473.

Arcipowski KM, Stunz LL, Graham JP, Kraus ZJ, Vanden Bush TJ, Bishop GA. Molecular mechanisms of TNFR-associated factor 6 (TRAF6) utilization by the oncogenic viral mimic of CD40, latent membrane protein 1 (LMP1). J Biol Chem. 2011 Mar 25;286(12):9948-55. Epub 2011 Jan 24. PubMed PMID: 21262968; PubMed Central PMCID: PMC3060549.

Graham JP, Arcipowski KM, Bishop GA. Differential B-lymphocyte regulation by CD40 and its viral mimic, latent membrane protein 1. Immunol Rev. 2010 Sep;237(1):226-48. Review. PubMed PMID: 20727039.

Abstracts:

Arcipowski K, Stunz L, Hostager B, Bishop G. Molecular mechanisms of TRAF6 activation by CD40 and its oncogenic viral mimic, LMP1. Autumn Immunology Conference. Chicago, IL. Oral and poster presentations, 2008.

Arcipowski K, Stunz L, Bishop G. Molecular mechanisms of TRAF6 utilization by the oncogenic viral mimic of CD40, LMP1. Autumn Immunology Conference. Chicago, IL. Oral and poster presentations, 2009.

Arcipowski K, Stunz L, Bishop G. Molecular mechanisms of TRAF6 utilization by the oncogenic viral mimic of CD40, LMP1. Keystone Symposia: Lymphocyte activation and gene expression. Breckenridge, CO. Poster presentation, 2010.

Arcipowski K, Stunz L, Graham J, Kraus Z, Vanden Bush T, Bishop G. Molecular mechanisms of TRAF6 utilization by the oncogenic viral mimic of CD40, LMP1. Autumn Immunology Conference. Chicago, IL. Oral and poster presentations, 2010.

Arcipowski K, Stunz L, Graham J, Kraus Z, Vanden Bush T, Bishop G. Molecular mechanisms of TRAF6 utilization by the oncogenic viral mimic of CD40, LMP1. All-Iowa Virology Symposium. Iowa City, IA. Oral presentation, 2010.

Arcipowski K, Bishop G. The role of TAK1 in LMP1-mediated B cell functions. Keystone Symposia: New Insights into Normal versus Dysregulated B Cell Function. Whistler, British Columbia, Canada. Poster presentation, 2011.

Arcipowski K, Xie P, Graham J, Kraus Z, Stunz L, Poovassery J, Smith S, Bishop G. Multiple functions for TRAFs in immune regulation. International TNF Conference. Hyogo, Japan. Oral presentation, 2011.



Honors and Awards

  • 2009 MCB Retreat Travel Award for best oral presentation
  • Helen C. Levitt Center Virology Travel Award
  • AAAS member through the AAAS/Science Program for Excellence in Science
  • 2009-10 Molecular and Cellular Biology Seminar and Workshop Committee
  • 2010-11 Member of the American Association of Immunologists (AAI)
  • 2010-11 Molecular and Cellular Biology Admissions Committee
  • 2010 NIH T32AI007533-12 Virology Training Grant
  • 2011-12 American Heart Association Midwest Affiliate Predoctoral Fellowshi
  • International Programs Graduate Travel Award
  • 2012 Travel Award for best poster presentation at the UI Center for Immunology & Immune-based Diseases Retreat
  • Molecular & Cellular Biology Scientists' Survival Skills Series Committee 2011-12