SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis

SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.     

Protective role of brain ascorbic acid content against lipid peroxidation

Summary The high ascorbic acid concentration in the brain inhibits lipid peroxidation induced by various agents in rat brain microsomes. The physiological importance of the fact is discussed.We thank Miss Zs. Mergl for skilful technical assistance.     

Changes in intracellular pH and cell volume during the early phase of DMSO-induced differentiation of Friend erythroleukemia cells

Changes in intracellular pH and water volume were measured after treatment of Friend erythroleukemia cells with 1.5% DMSO. It was found that a continuous decrease in pHi occurred, beginning 1 h after induction and a decline in pHi of 0.18 was measured after 9 h. In addition a decline in cellular water volume, of 12% only 15 min after induction, and 23% after 9 h, was observed.     

Capacity of purified Lyt-2+ T cells to mount primary proliferative and cytotoxic responses to Ia- tumour cells

Allogeneic gene products of the major histocompatibility complex, the HLA complex in man and the H-2 complex in mice, induce T lymphocytes to exert powerful mixed lymphocyte reactions (MLR) and cell-mediated lympholysis (CML). In mice, the subset of T cells carrying the L3T4 surface antigen but lacking the Lyt-2 antigen responds predominantly to H-2 class II (Ia) differences whereas the L3T4- Lyt-2+ subset reacts to class I (K/D) differences. For primary responses the stimulus for MLR and CML appears to be controlled by Ia+ cells of the macrophage/dendritic cell lineages, for both L3T4+ and Lyt-2+ cells. The finding that Ia+ cells are required for responses involving Lyt-2+ cells has been taken to imply that triggering of these cells is controlled by Ia-restricted L3T4+ cells. Lyt-2+ cells have thus come to be regarded as crippled cells which are heavily dependent on 'help' from other T cells. This well-entrenched view is challenged by evidence presented here that purified Lyt-2+ cells can give high primary responses to certain Ia- tumour cells in vitro.     

Present status of underwater medicine. Review of some challenging problems

Zusammenfassung Es wird eine Übersicht über den gegenwärtigen Stand der Unterwassermedizin gegeben. Besondere Berücksichtigung finden die in jüngster Zeit durchgeführten Forschungen, die die Grundlage für eine Erweiterung der Grenzen des Tieftauchens bereiteten, wie z.B. der 1972 durchgeführte Rekordtauchgang der Comex Gruppe, bei dem eine Tiefe von 2001 Fuss (610 m) in der Kammer erreicht wurde. Nach den in diesem Experiment erhobenen Befunden können ausgewählte und trainierte Taucher in einer Tiefe von 1400 Fuss (427 m) noch gut arbeiten und leben, wenn sie eine Helium-Sauerstoffmischung atmen. Die Ursachen des «Nervösen Hochdruck-Syndromes», sowie die kritische Volumentherorie vonMiller ⁶ als ein Erklärungsversuch für das Fehlen der narkotischen Wirkung von Helium unter hohem Druck im Vergleich zu Stickstoff werden diskutiert.

---

---

This paper was presented in part at the XXI International Congress of Aviation and Space Medicine, September 19, 1973 in Munich (Germany, Fed. Rep.).     

A new class of homoserine lactone quorum-sensing signals

Quorum sensing is a term used to describe cell-to-cell communication that allows cell-density-dependent gene expression. Many bacteria use acyl-homoserine lactone (acyl-HSL) synthases to generate fatty acyl-HSL quorum-sensing signals, which function with signal receptors to control expression of specific genes. The fatty acyl group is derived from fatty acid biosynthesis and provides signal specificity, but the variety of signals is limited. Here we show that the photosynthetic bacterium Rhodopseudomonas palustris uses an acyl-HSL synthase to produce p-coumaroyl-HSL by using environmental p-coumaric acid rather than fatty acids from cellular pools. The bacterium has a signal receptor with homology to fatty acyl-HSL receptors that responds to p-coumaroyl-HSL to regulate global gene expression. We also found that p-coumaroyl-HSL is made by other bacteria including Bradyrhizobium sp. and Silicibacter pomeroyi. This discovery extends the range of possibilities for acyl-HSL quorum sensing and raises fundamental questions about quorum sensing within the context of environmental signalling.