TRAF3 deficiency promotes metabolic reprogramming in B cells

Nurbek Mambetsariev,Alicia M Wallis,Gail A Bishop,Laura L Stunz,Wai W Lin

doi:10.1038/srep35349

Nurbek Mambetsariev, Alicia M Wallis + Show 3 more

Open Access

https://doi.org/10.1038/srep35349

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Abstract

The adaptor protein TNF receptor-associated factor 3 (TRAF3) is a critical regulator of B lymphocyte survival. B cell-specific TRAF3 deficiency results in enhanced viability and is associated with development of lymphoma and multiple myeloma. We show that TRAF3 deficiency led to induction of two proteins important for glucose metabolism, Glut1 and Hexokinase 2 (HXK2). This was associated with increased glucose uptake. In the absence of TRAF3, anaerobic glycolysis and oxidative phosphorylation were increased in B cells without changes in mitochondrial mass or reactive oxygen species. Chemical inhibition of glucose metabolism or glucose deprivation substantially attenuated the enhanced survival of TRAF3-deficient B cells, with a decrease in the pro-survival protein Mcl-1. Changes in Glut1 and Mcl-1 levels, glucose uptake and B cell number in the absence of TRAF3 were all dependent upon NF-κB inducing kinase (NIK). These results indicate that TRAF3 deficiency suffices to metabolically reprogram B cells, a finding that improves our understanding of the role of TRAF3 as a tumor suppressor, and suggests potential therapeutic strategies.

Highlights

TRAF3 deficiency in B cells dramatically alters survival, the metabolic changes associated with this phenotype have not been explored
B cells isolated from B-Traf3−/− mice had increased protein abundance (Fig. 1A) and mRNA expression (Fig. 1B) of Glut[1] and HXK2, compared to B cells isolated from wild type littermate controls (WT)
When imaged in vivo with positron emission tomography–computed tomography (PET-CT), older B-Traf3−/− mice took up more glucose tracer, with a significant increase in the spleen compared to WT mice (Supplementary Fig. S1)

Summary

Introduction

TRAF3 deficiency in B cells dramatically alters survival, the metabolic changes associated with this phenotype have not been explored. We show that TRAF3 deficiency was sufficient to induce expression of Glut[1] and HXK2 in B cells. This in turn led to an increase in glucose uptake. Our results show that the pre-malignant survival phenotype of TRAF3-deficient B cells is accompanied by an altered metabolic state. These findings have important implications for pathogenesis and treatment of B cell malignancies promoted by TRAF3 deficiency.

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