The deubiquitinase OTUD7B is shown to regulate the non-canonical NF-κB pathway by inhibiting TRAF3 proteolysis. The transcription factor NF-κB regulates many biological processes and — when deregulated — contributes to the pathogenesis of various diseases. This study shows that the deubiquitinase OTUD7B specifically controls one of the major pathways of NF-κB activation, the non-canonical or alternative pathway, by inhibiting TRAF3 proteolysis. OTUD7B deficiency in mice causes severe abnormalities in antibody production and intestinal homeostasis. These findings point to OTUD7B as a potentially attractive therapeutic target for drugs to boost mucosal immunity and treat diseases associated with the non-canonical NF-κB pathway. The non-canonical NF-κB pathway forms a major arm of NF-κB signalling that mediates important biological functions, including lymphoid organogenesis, B-lymphocyte function, and cell growth and survival1,2,3. Activation of the non-canonical NF-κB pathway involves degradation of an inhibitory protein, TNF receptor-associated factor 3 (TRAF3), but how this signalling event is controlled is still unknown1,2. Here we have identified the deubiquitinase OTUD7B as a pivotal regulator of the non-canonical NF-κB pathway. OTUD7B deficiency in mice has no appreciable effect on canonical NF-κB activation but causes hyperactivation of non-canonical NF-κB. In response to non-canonical NF-κB stimuli, OTUD7B binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant non-canonical NF-κB activation. Consequently, the OTUD7B deficiency results in B-cell hyper-responsiveness to antigens, lymphoid follicular hyperplasia in the intestinal mucosa, and elevated host-defence ability against an intestinal bacterial pathogen, Citrobacter rodentium. These findings establish OTUD7B as a crucial regulator of signal-induced non-canonical NF-κB activation and indicate a mechanism of immune regulation that involves OTUD7B-mediated deubiquitination and stabilization of TRAF3.

Whether or not FLT3 mutations are present and expressed within a leukemic hematopoietic stem cell has engendered some controversy. New evidence has now been presented on this issue that could change the way we manage the disease in the future.

Regulatory T cells (T_reg cells) control different aspects of immune responses, but how the effector functions of T_reg cells are regulated is incompletely understood. Here we identified TNF receptor–associated factor 3 (TRAF3) as a regulator of T_reg cell function. T_reg cell–specific ablation of TRAF3 impaired CD4 T cell homeostasis, characterized by an increase in the Th1 type of effector/memory T cells. Moreover, the ablation of TRAF3 in T_reg cells resulted in increased antigen-stimulated activation of follicular T helper cells (T_FH cells), coupled with heightened formation of germinal centers and production of high-affinity IgG antibodies. Although the loss of TRAF3 did not reduce the overall frequency of T_reg cells, it attenuated the antigen-stimulated production of follicular T_reg cells (T_FR cells). TRAF3 signaling in T_reg cells was required to maintain high level expression of inducible co-stimulator (ICOS), which in turn was required for T_FR cell generation and inhibition of antibody responses. These findings establish TRAF3 as a mediator of T_reg cell function in the regulation of antibody responses and suggest a role for TRAF3 in mediating ICOS expression in T_reg cells.

Tumor suppressor p53-dependent apoptosis is critical in suppressing tumorigenesis. Previously, we reported that DNA double-strand breaks (DSBs) at the V(D)J recombination loci induced genomic instability in the developing lymphocytes of nonhomologous end-joining (NHEJ)–deficient, p53-deficient mice, which led to rapid lymphomagenesis. To test the ability of p53-dependent cell cycle arrest to suppress tumorigenesis in the absence of apoptosis in vivo, we crossbred NHEJ-deficient mice into a mutant p53R172P background; these mice have defects in apoptosis induction, but not cell cycle arrest. These double-mutant mice survived longer than NHEJ/p53 double-null mice and, remarkably, were completely tumor free. We detected accumulation of aberrant V(D)J recombination–related DSBs at the T cell receptor (TCR) locus, and high expression levels of both mutant p53 and cell cycle checkpoint protein p21, but not the apoptotic protein p53-upregulated modulator of apoptosis. In addition, a substantial number of senescent cells were observed among both thymocytes and bone marrow cells. Cytogenetic studies revealed euploidy and limited chromosomal breaks in these lymphoid cells. The results indicate that precursor lymphocytes, which normally possess a high proliferation potential, are able to withdraw from the cell cycle and undergo senescence in response to the persistence of DSBs in a p53–p21–dependent pathway; this is sufficient to inhibit oncogenic chromosomal abnormality and suppress tumorigenesis.

Valproic acid (VPA) is widely recognized for its use in the control of epilepsy and other neurological disorders in the past 50 years. Recent evidence has shown the potential of VPA in the control of certain cancers, owed in part to its role in modulating epigenetic changes through the inhibition of histone deacetylases, affecting the expression of genes involved in the cell cycle, differentiation, and apoptosis. The direct impact of VPA in cells of the immune system has only been explored recently. In this review, we discuss the effects of VPA in the suppression of some activation mechanisms in several immune cells that lead to an anti-inflammatory response. As expected, immune cells are not exempt from the effect of VPA, as it also affects the expression of genes of the cell cycle and apoptosis through epigenetic modifications. In addition to inhibiting histone deacetylases, VPA promotes RNA interference, activates histone methyltransferases, or represses the activation of transcription factors. However, during the infectious process, the effectiveness of VPA is subject to the biological nature of the pathogen and the associated immune response; this is because VPA can promote the control or the progression of the infection. Due to its various effects, VPA is a promising alternative for the control of autoimmune diseases and hypersensitivity and needs to be further explored.