The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development
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TRAF3 tamps down B cell responsiveness to IL-6 to prevent excessive generation of antibody-producing cells.
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Loss-of-function mutations of TRAF3, a negative regulator of IL-6-STAT3 signaling, are observed in B-cell lymphoma and multiple myeloma patients.
“LOF mutations of TRAF3, a negative regulator of IL-6–STAT3 signaling, are observed in B-cell lymphoma and multiple myeloma patients (122, 273, 274).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [122]
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“More recently, PTPN22 and TNF receptor-associated factor (TRAF)3 have been put forward as inhibitors of IL-6R signaling in B cells and plasma cell differentiation [43].”
BackgroundWhillock, A. L., Mambetsariev, N., Lin, W., Stunz, L. L., & Bishop, G. A. (2019) · Scientific Reports · doi:10.1038/s41598-019-49390-9 · Cited by 23 · see citing works
Self-citationBangalore-Prakash, P., Stunz, L. L., Mambetsariev, N., Whillock, A. L., Hostager, B. S., & Bishop, G. A. (2017) · Blood Advances · doi:10.1182/bloodadvances.2017009670 · Cited by 21 · see citing works
Self-citationLim, J., & Kim, K.-W. (2019) · Scientific Reports · doi:10.1038/s41598-019-39132-2 · Cited by 22 · see citing works
Single-cell landscape of idiopathic multicentric Castleman disease in identical twins
Chan, J. Y., Loh, J. W., Lim, J. Q., Liany, H., Lee, E. C. Y., Lee, J. Y., Kannan, B., Lim, B. Y., Guo, Z., Lim, K. M. H., et al. (2024) · Blood · doi:10.1182/blood.2023021992 · Cited by 20 · see citing works
Pedros, C., Altman, A., & Kong, K. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02412 · Cited by 20 · see citing works
“Conversely, TRAF3 can inhibit IL-6R signaling in B cells (170) and negatively regulate OX40-induced NFκB signaling in HEK293T cells (217).”
BackgroundBohl, S., Schmalbrock, L. K., Bauhuf, I., Meyer, T., Dolnik, A., Szyska, M., Blätte, T. J., Knödler, S., Röhner, L., Miller, D., et al. (2021) · Blood Advances · doi:10.1182/bloodadvances.2020003541 · Cited by 19 · see citing works
Wallis, A. M., & Bishop, G. A. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.2mir0817-339rr · Cited by 14 · see citing works
Self-citationFomicheva, M., & Macara, I. G. (2020) · eLife · doi:10.7554/elife.63603 · Cited by 13 · see citing works
TRAF3 enhances type I interferon receptor signaling in T cells by modulating the phosphatase PTPN22
Hornick, E. E., Wallis, A. M., & Bishop, G. A. (2022) · Science Signaling · doi:10.1126/scisignal.abn5507 · Cited by 13 · see citing works
“For example, TRAF3 facilitates the association of the negative regulator PTPN22 with JAK1 at the interleukin-6 (IL-6) receptor in B cells to decrease signaling (17).”
BackgroundSelf-citationActivated B lymphocytes and tumor cell lysate as an effective cellular cancer vaccine
Oxley, K. L., Hanson, B. M., Zani, A., & Bishop, G. A. (2021) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-021-02914-7 · Cited by 11 · see citing works
Self-citationMultiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR
Li, H., Hostager, B. S., Arkee, T., & Bishop, G. A. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101097 · Cited by 10 · see citing works
Self-citationKimura, M., Nagashima, H., Okuyama, Y., Ishii, N., & So, T. (2018) · International Immunology · doi:10.1093/intimm/dxy029 · Cited by 9 · see citing works
TRAF3: A novel regulator of mitochondrial physiology and metabolic pathways in B lymphocytes
Jung, J., Gokhale, S., & Xie, P. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1081253 · Cited by 7 · see citing works
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Hornick, E. E., Stunz, L. L., Sabree, S. A., Wu, X., Witzig, T. E., & Bishop, G. A. (2022) · Cancers · doi:10.3390/cancers14205029 · Cited by 5 · see citing works
“We previously reported that mice with a B cell-specific TRAF3 deficiency have a significantly expanded plasma cell compartment, which is dependent on enhanced signaling by IL-6R [5].”
BackgroundInfluentialSelf-citationArkee, T., Hornick, E. E., & Bishop, G. A. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107737 · Cited by 4 · see citing works
“Interactions between TRAF3 and the tyrosine phosphatase PTPN22 restrain IL-6R signaling in B cells (49) and enhance TCR-mediated Lck activation and type I IFN signaling in T cells (4, 14).”
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“…it is essential for the terminal differentiation of B cells into antibody-secreting plasma cells, and, as mentioned earlier, it collaborates with TGF-β to drive the differentiation of pathogenic Th17 cells, thus linking innate signals to both humoral and cellular inflammatory pathways [167, 168].”
Targeting transcription-replication conflicts using G-quadruplexes stabilizers in multiple myeloma
Dutrieux, L., Ovejero, S., Guillemin, A., Zellagui, M. L., Bruyne, E. D., Muylaert, C., Hemelrijck, L. A. V., Lin, Y., Loughran, E., Choquet, A., et al. (2025) · Blood Neoplasia · doi:10.1016/j.bneo.2025.100072 · Cited by 3 · see citing works
Longitudinal study of living kidney donor glomerular dynamics after nephrectomy
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Histopathological evaluation of periapical lesions in developing molars of young male rats
Gelio, M. B., Nakazone, P. A., da Fonseca, T. S., Silva, E. C. A., Sasso‐Cerri, E., & Cerri, P. S. (2025) · Archives of Oral Biology · doi:10.1016/j.archoralbio.2025.106222 · Cited by 1 · see citing works
Reduction of TRAF3 by heterozygosity or aging impacts B cell function
Hornick, E. E., Oxley, K. L., Wieting, N., Treco, E. N., Hostager, B. S., & Bishop, G. A. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2507217122 · Cited by 1 · see citing works
“Work from our laboratory demonstrated that TRAF3 deficiency in B cells removes a crucial brake on IL - 6R signaling, leading to a nearly twofold increase in PCs in B - Traf3 −/− mice compared to WT littermate controls (6).”
Self-citationRole of TNF-Receptor-Associated Factor (TRAF3) in the Immune System Cells (Review)
Anufriieva, Y., Hasiuk, O., & Бесчасный, С. П. (2020) · Ukraïnsʹkij žurnal medicini bìologìï ta sportu · doi:10.26693/jmbs05.06.329
“IL-6R – цитокіновий рецептор, стосовно якого встановлена достеменна регулююча роль TRAF3 у В-клітинах.”
InfluentialMambetsariev, N., & Bishop, G. A. (2016) · Springer eBooks · doi:10.1007/978-1-4614-6438-9_101728-1
Self-citationMambetsariev, N., & Bishop, G. A. (2017) · Springer eBooks · doi:10.1007/978-3-319-67199-4_101728
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Hornick, E. E., Oxley, K. L., Debreceni, I. L., Wieting, N., Ybarra, T. K., Hostager, B. S., Lieberman, S. M., & Bishop, G. A. (2026) · The Journal of Immunology · doi:10.1093/jimmun/vkag049
Self-citationTriantafillidi, D., Tziouvara, V., Pontikas, A., Akritidis, A., Antonatos, C., Zacharopoulou, A., Tsiogka, A., Kleidona, I. A., Grafanaki, K., Chrysospathi, A., et al. (2026) · Genes · doi:10.3390/genes17050575
“…is further controlled by intracellular negative regulators; protein tyrosine phosphatase non-receptor type 22 (PTPN22) can be recruited via TNF receptor-associated factor 3 (TRAF3) to the receptor complex, thereby attenuating IL6-dependent signaling through dephosphorylation of JAK1 and STAT3 [8].”
- Authors
- Lin, W. W., Yi, Z., Stunz, L. L., Maine, C. J., Sherman, L. A., & Bishop, G. A.
- Affiliations
- University of Iowa (US)
- Scripps Research Institute (US)
- Corresponding author
- Bishop, Gail A.
- Venue
- Science Signaling
- Published
- 2015-09
- Volume
- 8
- Issue
- 392
- Pages
- ra88-ra88
- ISSN
- 1937-9145 (ISSN-L)
- 1945-0877
- PMC
- PMC4720969
- OpenAlex
- W2258433604
- Cited by
- 50
- References
- 56
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 7 · 2017: 4 · 2016: 6 · 2015: 2
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Signaling (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (CA099997, AI28847, P50 CA97274, DK050824, P30CA086862, T32 AI007260)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- TRAF3, plasma cell differentiation, B cells, PTPN22, JAK1, STAT3 phosphorylation, multiple myeloma, B cell homeostasis, adaptor proteins, cytokine signaling inhibition
- MeSH terms
- Animals, Humans, Plasma Cells, Signal Transduction, Mice, Knockout, Receptors, Interleukin-6, TNF Receptor-Associated Factor 3, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 22
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