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Fungal infections constitute a severe health threat, especially to people with an impaired immune status, as observed after HIV infection (1), immune suppression (2), or primary immune deficiencies (3). Candida [...], Fungal infections claim an estimated 1.5 million lives each year. Mechanisms that protect from fungal infections are still elusive. Recognition of fungal pathogens relies on C-type lectin receptors (CLRs) and their downstream signaling kinase SYK. Here we report that the E3 ubiquitin ligase CBLB controls proximal CLR signaling in macrophages and dendritic cells. We show that CBLB associates with SYK and ubiquitinates SYK, dectin-1, and dectin-2 after fungal recognition. Functionally, CBLB deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. Genetic deletion of Cblb protects mice from morbidity caused by cutaneous infection and markedly improves survival after a lethal systemic infection with Candida albicans. On the basis of these findings, we engineered a cell-permeable CBLB inhibitory peptide that protects mice from lethal C. albicans infections. We thus describe a key role for Cblb in the regulation of innate antifungal immunity and establish a novel paradigm for the treatment of fungal sepsis.

Bone-mass regulation depends on the dynamic balance between bone formation and bone resorption, which are driven by osteoblast activation and osteoclast activation, respectively. RANKL is a central positive regulator of [...], Tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL) regulates multiple physiological or pathological functions, including osteoclast differentiation and osteoporosis. TNFRSF11A (also called RANK) is considered to be the sole receptor for RANKL. Herein we report that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. RANKL binding to LGR4 activates the Gaq and GSK3-p signaling pathway, an action that suppresses the expression and activity of nuclear factor of activated T cells, cytoplasmic, calcineurindependent 1 (NFATC1) during osteoclastogenesis. Both whole-body ([Lgr4.sup.-/-]) and monocyte conditional knockout mice of Lgr4 (Lgr4 CKO) exhibit osteoclast hyperactivation (including elevation of osteoclast number, surface area, and size) and increased bone erosion. The soluble LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Moreover, LGR4-ECD therapeutically abrogated RANKL-induced bone loss in three mouse models of osteoporosis. Therefore, LGR4 acts as a second RANKL receptor that negatively regulates osteoclast differentiation and bone resorption.

RANKL (also known as TNFSF11) is a member of the tumor necrosis factor superfamily and, after ligation with its cognate receptor RANK (also known as TNFRSF11a), is a potent stimulator [...], Hepatic insulin resistance is a driving force in the pathogenesis of type 2 diabetes mellitus (T2DM) and is tightly coupled with excessive storage of fat and the ensuing inflammation within the liver (1-3). There is compelling evidence that activation of the transcription factor nuclear factor-κB (NF-κB) and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic insulin resistance and b-cell dysfunction, although the molecular mechanisms involved are incompletely understood (3-6). We here test the hypothesis that receptor activator of NF-κB ligand (RANKL), a prototypic activator of NF-κB, contributes to this process using both an epidemiological and experimental approach. In the prospective population-based Bruneck Study, a high serum concentration of soluble RANKL emerged as a significant (P < 0.001) and independent risk predictor of T2DM manifestation. In close agreement, systemic or hepatic blockage of RANKL signaling in genetic and nutritional mouse models of T2DM resulted in a marked improvement of hepatic insulin sensitivity and amelioration or even normalization of plasma glucose concentrations and glucose tolerance. Overall, this study provides evidence for a role of RANKL signaling in the pathogenesis of T2DM. If so, translation to the clinic may be feasible given current pharmacological strategies to lower RANKL activity to treat osteoporosis.

ALCLs are T cell lymphomas (1), (2) comprising 10-20% of all non-Hodgkin's lymphoma cases in children and 3% in adults (3). About half of ALCL cases are positive for the [...], Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin--anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK--triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-[ALK.sup.+] ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.

In vitro osteoclast differentiation is induced by the cell-cell contact between osteoclast precursor cells of the monocyte/macrophage lineage and anchorage-dependent mesenchymal cells in bone, which include osteoblasts and bone marrow [...], Osteocytes embedded in bone have been postulated to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. We find here that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells. Furthermore, the severe osteopetrotic phenotype that we observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling in vivo.

Author(s): Liyong Zhang [1, 2, 5]; Michael S Anglesio [3, 5]; Maureen O'Sullivan [3]; Fan Zhang [3]; Ge Yang [2]; Renu Sarao [1, 2]; Mai P Nghiem [1, 2]; Shane [...]

Author(s): Karin Loser [1, 2]; Annette Mehling [1]; Stefanie Loeser [3]; Jenny Apelt [1]; Annegret Kuhn [4]; Stephan Grabbe [5]; Thomas Schwarz [6]; Josef M Penninger [3]; Stefan Beissert (corresponding [...]

Author(s): Teiji Wada (corresponding author) [1]; Tomoki Nakashima [1]; Antonio J Oliveira-dos-Santos [2]; Juerg Gasser [3]; Hiromitsu Hara [1]; Georg Schett [4]; Josef M Penninger (corresponding author) [1] The accumulation [...]

Author(s): Urs Eriksson (corresponding author) [1, 2]; Romeo Ricci [1]; Lukas Hunziker [2]; Michael O Kurrer [3]; Gavin Y Oudit [4]; Tania H Watts [5]; Ivo Sonderegger [6]; Kurt Bachmaier [...]

Author(s): Ursula Danilczyk [1]; Josef Penninger [1] The observation that salt intake is associated with hypertension is thousands of years old. The Huang Ti Nei Ching , the Yellow Emperor's [...]

Author(s): Kurt Bachmaier [1]; Jenny Le [1]; Josef M. Penninger [1] To the editor Supporters of the 'new germ theory' argue that common human diseases are caused by infectious agents. [...]

Author(s): Urs Eriksson; Romeo Ricci; Lukas Hunziker; Michael O Kurrer; Gavin Y Oudit; Tania H Watts; Ivo Sonderegger; Kurt Bachmaier; Manfred Kopf; Josef M Penninger Nat. Med. 9, 1484-1490 (2003) [...]

Transformation and cancer growth are regulated by the coordinate actions of oncogenes and tumor suppressors. Here, we show that the novel E3 ubiquitin ligase HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice results in the development of spontaneous, late-onset cancer. A second hit from either environmental triggers or genetic heterozygosity of another tumor suppressor, p53, markedly increased tumor incidence in a Hace1-deficient background. Re-expression of HACE1 in human tumor cells directly abrogates in vitro and in vivo tumor growth, whereas downregulation of HACE1 via siRNA allows non-tumorigenic human cells to form tumors in vivo. Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. Thus, HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers. [ABSTRACT FROM AUTHOR]

Infections are thought to be important in the pathogenesis of many heart diseases. Coxsackievirus B3 (CVB3) has been linked to chronic dilated cardiomyopathy, a common cause of progressive heart disease, heart failure and sudden death. We show here that the sarcoma (Src) family kinase Lck (p56lck) is required for efficient CVB3 replication in T-cell lines and for viral replication and persistence in vivo. Whereas infection of wild-type mice with human pathogenic CVB3 caused acute and very severe myocarditis, meningitis, hepatitis, pancreatitis and dilated cardiomyopathy, mice lacking the p56lck gene were completely protected from CVB3-induced acute pathogenicity and chronic heart disease. These data identify a previously unknown function of Src family kinases and indicate that p56lck is the essential host factor that controls the replication and pathogenicity of CVB3. [ABSTRACT FROM AUTHOR]