The role of different TRAF3 mutants in CD40 stimulation

Our lab studies the role of different TNF receptor associated factors (TRAFs) in lymphocyte activation. My work focuses on TRAF3. It is an adaptor protein that associates with CD40, BAFF-R to mediate various downstream singling events in activated B cells such as NF-κB1 & 2, JNK and ERK activation. TRAF3 function as a negative regulator of these receptors. Upon receptor stimulation TRAF3 is recruited to the receptor signaling complex, modified through ubiquitination and degraded by proteosomes. Therefore, mutations that are associated with TRAF3 will have a significant impact on these signaling pathways. A genome wide study of multiple myeloma patients performed by Dr. Bersagels’ lab identified several TRAF3 mutations, ranging from point mutations to large truncations. These mutations result in constitutive activation NF-κB2 pathway.

The aim of my work is to delineate how different TRAF3 mutants contributes to constitutive activation of NF-kB2 pathway and to further characterize which other signaling pathways are affected by different TRAF3 mutants.

Mambetsariev N, Lin WW, Wallis AM, Stunz LL, Bishop GA. TRAF3 deficiency promotes metabolic reprogramming in B cells. Sci Rep. 2016 Oct 18;6:35349. doi:10.1038/srep35349. PubMed PMID: 27752131; PubMed Central PMCID: PMC5082756.

Mambetsariev N, Lin WW, Stunz LL, Hanson BM, Hildebrand JM, Bishop GA. Nuclear TRAF3 is a negative regulator of CREB in B cells. Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):1032-7. doi: 10.1073/pnas.1514586113. PubMed PMID: 26755589; PubMed Central PMCID: PMC4743771.

Lin WW, Yi Z, Stunz LL, Maine CJ, Sherman LA, Bishop GA. The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development. Sci Signal. 2015 Sep 1;8(392):ra88. doi: 10.1126/scisignal.aaa5157. PubMed PMID: 26329582; PubMed Central PMCID: PMC4720969

Lin WW, Hostager BS, Bishop GA. TRAF3, ubiquitination, and B-lymphocyte regulation. Immunol Rev. 2015 Jul;266(1):46-55. doi: 10.1111/imr.12299. PubMed PMID: 26085206; PubMed Central PMCID: PMC4473794

Yi Z, Lin WW, Stunz LL, Bishop GA. The adaptor TRAF3 restrains the lineage determination of thymic regulatory T cells by modulating signaling via the receptor for IL-2. Nat Immunol. 2014 Sep;15(9):866-74. doi: 10.1038/ni.2944. Epub 2014 Jul 20. PubMed PMID: 25029551; PubMed Central PMCID: PMC4139452.

Yi Z, Stunz LL, Lin WW, Bishop GA. TRAF3 regulates homeostasis of CD8+ central memory T cells. PLoS One. 2014 Jul 10;9(7):e102120. doi:10.1371/journal.pone.0102120. eCollection 2014. PubMed PMID: 25010048; PubMed Central PMCID: PMC4092107.

Yi Z, Lin WW, Stunz LL, Bishop GA. Roles for TNF-receptor associated factor 3 (TRAF3) in lymphocyte functions. Cytokine Growth Factor Rev. 2014 Apr;25(2):147-56. doi: 10.1016/j.cytogfr.2013.12.002. Epub 2013 Dec 25. PubMed PMID: 24433987; PubMed Central PMCID: PMC3999169.

Lin WW, Hildebrand JM, Bishop GA. A Complex Relationship between TRAF3 and Non-Canonical NF-κB2 Activation in B Lymphocytes. Front Immunol. 2013 Dec 20;4:477. doi: 10.3389/fimmu.2013.00477. eCollection 2013. PubMed PMID: 24391649; PubMed Central PMCID: PMC3868921.

Jellusova J, Miletic AV, Cato MH, Lin WW, Hu Y, Bishop GA, Shlomchik MJ Rickert RC. Context-specific BAFF-R signaling by the NF-κB and PI3K pathways. Cell Rep. 2013 Nov 27;5(4):1022-35. doi: 10.1016/j.celrep.2013.10.022. Epub 2013 Nov 14. PubMed PMID: 24239354; PubMed Central PMCID: PMC3887557.

Hildebrand JM, Luo Z, Manske MK, Price-Troska T, Ziesmer SC, Lin W, Hostager BS, Slager SL, Witzig TE, Ansell SM, Cerhan JR, Bishop GA, Novak AJ. A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling. J Exp Med. 2010 Nov 22;207(12):2569-79. doi: 10.1084/jem.20100857. Epub 2010 Nov 1. PubMed PMID: 21041452; PubMed Central PMCID: PMC2989778.