B cell endosomal RAB7 promotes TRAF6 K63 polyubiquitination and NF-κB activation for antibody class-switching

Hui Yan, Maria Fernandez, Jingwei Wang, Shuai Wu, Rui Wang, Zheng Lou, Justin B. Moroney, Carlos E. Rivera, Julia R. Taylor, Huoqun Gan, Hong Zan, Dmytro Kolvaskyy, Dongfang Liu, Paolo Casali, Zhenming Xu

Research output: Contribution to journalArticle

Abstract

Upon activation by CD40 or TLR signaling, B lymphocytes activate NF-κB to induce activation-induced cytidine deaminase and, therefore, Ig class switch DNA recombination, as central to the maturation of the Ab and autoantibody responses. In this study, we show that NF-κB activation is boosted by colocalization of engaged immune receptors, such as CD40, with RAB7 small GTPase on mature endosomes, in addition to signals emanating from the receptors localized on the plasma membrane, in mouse B cells. In mature endosomes, RAB7 directly interacts with TRAF6 E3 ubiquitin ligase, which catalyzes K63 polyubiquitination for NF-κB activation. RAB7 overexpression in Cd19+/creRosa26fl-STOP-fl-Rab7 mouse B cells upregulates K63 polyubiquitination activity of TRAF6, enhances NF-κB activation and activation-induced cytidine deaminase induction, and boosts IgG Ab and autoantibody levels. This, together with the extensive intracellular localization of CD40 and the strong correlation of RAB7 expression with NF-κB activation in mouse lupus B cells, shows that RAB7 is an integral component of the B cell NF-κB activation machinery, likely through interaction with TRAF6 for the assembly of "intracellular membrane signalosomes".

Original languageEnglish (US)
Pages (from-to)1146-1157
Number of pages12
JournalJournal of Immunology
Volume204
Issue number5
DOIs
StatePublished - Mar 1 2020

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Yan, H., Fernandez, M., Wang, J., Wu, S., Wang, R., Lou, Z., Moroney, J. B., Rivera, C. E., Taylor, J. R., Gan, H., Zan, H., Kolvaskyy, D., Liu, D., Casali, P., & Xu, Z. (2020). B cell endosomal RAB7 promotes TRAF6 K63 polyubiquitination and NF-κB activation for antibody class-switching. Journal of Immunology, 204(5), 1146-1157. https://doi.org/10.4049/jimmunol.1901170