Microglia are crucial for the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Here, we show that the E3 ubiquitin ligase Peli1 is abundantly expressed in microglia and serves as a pivotal mediator of microglial activation during the course of EAE induction. Peli1 mediates the induction of chemokines and proinflammatory cytokines in microglia and, thereby, promotes recruitment of T cells into the central nervous system. Peli1-deficient mice are refractory to EAE induction despite their competent production of Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms HHS Public Access

Deubiquitinases (DUBs) represent a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized an E3 ubiquitin ligase, MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.

Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia. Tumor resection leads to cure. We investigated the clinical characteristics of TIO, diagnostic methods, and course after tumor resection in Beijing, China, and compared them with 269 previous published reports of TIO. A total of 94 patients with adult-onset hypophosphatemic osteomalacia were seen over a 6-year period (January, 2004 to May, 2010 in Peking Union Medical College Hospital. After physical examination (PE), all patients underwent technetium-99m octreotide scintigraphy ( 99 Tc m -OCT). Tumors were removed after localization. The results demonstrated that 46 of 94 hypophosphatemic osteomalacia patients had high uptake in 99 Tc m -OCT imaging. Forty of them underwent tumor resection with the TIO diagnosis established in 37 patients. In 2 patients, the tumor was discovered on PE but not by 99 Tc m -OCT. The gender distribution was equal (M/F ¼ 19/20). Average age was 42 AE 14 years. In 35 patients (90%), the serum phosphorus concentration returned to normal in 5.5 AE 3.0 days after tumor resection. Most of the tumors (85%) were classified as phosphaturic mesenchymal tumor (PMT) or mixed connective tissue variant (PMTMCT). Recurrence of disease was suggested in 3 patients (9%). When combined with the 269 cases reported in the literature, the mean age and sex distribution were similar. The tumors were of bone (40%) and soft tissue (55%) origins, with 42% of the tumors being found in the lower extremities. In summary, TIO is an important cause of adult-onset hypophosphatemia in China. 99 Tc m -OCT imaging successfully localized the tumor in the overwhelming majority of patients. Successful removal of tumors leads to cure in most cases, but recurrence should be sought by long-term follow-up. ß

The noncanonical NF-κB pathway forms a major arm of NF-κB signaling that mediates important biological functions, including lymphoid organogenesis, B lymphocyte function, and cell growth and survival1-3. Activation of the noncanonical NF-κB pathway involves degradation of an inhibitory protein, TNF receptor associated factor 3 (TRAF3), but how this signaling event is controlled is still unknown1,2. Here we have identified the deubiquitinase Otud7b as a pivotal regulator of the noncanonical NF-κB pathway. Otud7b deficiency in mice has no appreciable effect on canonical NF-κB activation but causes hyper-activation of noncanonical NF-κB. In response to noncanonical NF-κB stimuli, Otud7b binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant noncanonical NF-κB activation. Consequently, the Otud7b deficiency results in B-cell hyperresponsiveness to antigens, lymphoid follicular hyperplasia in the intestinal mucosa, and elevated host-defense ability against an intestinal bacterial pathogen, Citrobacter rodentium. These findings establish Otud7b as a crucial regulator of signal-induced noncanonical NF-κB activation and suggest a mechanism of immune regulation that involves Otud7b-mediated deubiquitination and stabilization of TRAF3.

Highlights d Peripheral CD4 + T cells control stress-induced anxiety-like behavior d Mitochondrial fission in peripheral CD4 + T cell causes severe anxiety symptoms d T cell-derived xanthine acts on the oligodendrocytes in the left amygdala d IRF-1 controls purine synthesis in CD4 + T cells and triggers the onset of anxiety

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NF-κB transcription factors are pivotal regulators of innate and adaptive immune responses, and perturbations of NF-κB signaling contribute to the pathogenesis of immunological disorders. NF-κB is a well-known proinflammatory mediator, and its deregulated activation is associated with the chronic inflammation of autoimmune diseases. Paradoxically, NF-κB plays a crucial role in the establishment of immune tolerance, including both central tolerance and the peripheral function of regulatory T (Treg) cells. Thus, defect or deregulated activation of NF-κB may contribute to autoimmunity and inflammation, highlighting the importance of tightly controlled NF-κB signaling. This review will focus on the recent progress regarding NF-κB regulation and its association with autoimmunity.

Signal transduction from toll-like receptors (TLRs) is important for innate immunity against infections, but deregulated TLR signaling contributes to inflammatory disorders. Here we show that myeloid cell-specific ablation of TRAF2 greatly promotes TLR-stimulated proinflammatory cytokine expression in macrophages and exacerbates colitis in an animal model of inflammatory bowel disease. TRAF2 deficiency does not enhance upstream signaling events, but it causes accumulation of two transcription factors, c-Rel and IRF5, known to mediate proinflammatory cytokine induction. Interestingly, TRAF2 controls the fate of c-Rel and IRF5 via a proteasome-dependent mechanism that also requires TRAF3 and the E3 ubiquitin ligase cIAP. We further show that TRAF2 also regulates inflammatory cytokine production in tumor-associated macrophages and facilitates tumor growth. These findings demonstrate an unexpected anti-inflammatory function of TRAF2 and suggest a proteasome-dependent mechanism that limits the proinflammatory TLR signaling.