TRAF3 deficiency promotes metabolic reprogramming in B cells

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.

Metabolic abnormalities and oxidative stress in lupus

“…Another recently reported regulator of B cell metabolism is the metabolic sensor Gsk3 [14], which was shown to limit glucose consumption and maintain quiescence. Along the same lines, B cell-specific deletion of the adaptor protein Traf3 results in enhanced B cell survival, which depends on elevated glucose metabolism, and is achieved through the upregulation of Glut1 and hexokinase 2 (Hk2), an enzyme that catalyzes the first step in glycolysis [15]. It will be of interest to determine whether the expression of these regulatory factors is negatively affected in animal models of lupus and in patients with SLE.…”

The role of metabolic reprogramming in γ‐herpesvirus‐associated oncogenesis

“…Furthermore, we have identified a mutual exclusivity relationship between LMP1 expression and genetic inactivation of TRAF3 in NPCs . TRAF3 deficiency has been reported to promote glycolysis . Moreover, we have found that LMP1 upregulates Myc and HIF‐1α expression and induces FGF2/FGFR1 signalling activity .…”

The oncogenic membrane protein LMP1 sequesters TRAF3 in B-cell lymphoma cells to produce functional TRAF3 deficiency

“…This metabolic reprogramming involves enhanced expression of the glucose transporter Glut1 and the glycolytic enzyme hexokinase 2. 30 Tumor cells exhibit increased glucose metabolism downstream of various alterations, so we could not easily test whether LMP1 expression also induces this property in BCL line models, but it is an intriguing possibility.…”

“…These include constitutive noncanonical NF-kB2 activation, altered nuclear cyclic adenosine 59-monophosphate response element-binding protein (CREB) -mediated transcription of genes encoding pro-survival proteins, increased interleukin-6 receptor (IL-6R) signaling and enhanced glucose metabolism. [27][28][29][30] When the B-Traf3 2/2 mouse was first reported, 21 inactivating mutations in the human TRAF3 gene were also noted, associated with multiple myeloma (MM). 31,32 This has now been observed in multiple studies; such mutations are one of the top 11 seen in 66% of human MM.…”