Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181

NF-κB activation downstream of antigen receptor engagement is a highly regulated event required for lymphocyte activation during the adaptive immune response. The pathway is often dysregulated in lymphoma, leading to constitutive NF-κB activity that supports the aberrant proliferation of transformed lymphocytes. To identify novel regulators of antigen receptor signaling to NF-κB, we developed bioluminescence resonance energy transfer-based interaction cloning (BRIC), a screening strategy that can detect protein-protein interactions in live mammalian cells in a high-throughput manner. Using this strategy, we identified the RING finger protein RNF181 as an interactor of CARD11, a key signaling scaffold in the antigen receptor pathway. We present evidence that RNF181 functions as an E3 ubiquitin ligase to inhibit antigen receptor signaling to NF-κB downstream of CARD11. The levels of the obligate signaling protein Bcl10 are reduced by RNF181 even prior to signaling, and Bcl10 can serve as a substrate for RNF181 E3 ligase activity in vitro. Furthermore, RNF181 limits the proliferation of human diffuse large B cell lymphoma cells that depend upon aberrant CARD11 signaling to NF-κB for growth and survival in culture. Our results define a new regulatory checkpoint that can modulate the output of CARD11 signaling to NF-κB in both normal and transformed lymphocytes.     

The Elementary Nervous System Revisited

Parker's theory of the origin of the nervous system is discussedalong with later interpretations. Attention today has shiftedfrom the cellular to the molecular level, and it has becomeclear that many of the molecules and mechanisms thought of astypically neuronal have homologs or counterparts in non-nervouscells and unicellular organisms. This applies to signallingchemicals, receptors, second messenger systems and ion channels,and also to the production of electrical events. Parker's viewof sponges as a group lacking nerves but possessing independenteffectors is still acceptable, but some sponges (and also higheranimals) employ non-nervous signalling pathways to coordinatetheir effectors. Thus, nerves are not always necessary for coordinatedbehavior. Cnidarians like hydra have seemingly simple, two-dimensionalnervous systems with little or no centralization, but even suchsystems can be surprisingly complex, and the more advanced cnidariansshow neurophysiological specializations as sophisticated asthose of many higher invertebrates. Examples of ingenious cnidariansolutions to behavioral problems are given. No existing animalshave ‘elementary’ nervous systems if that term impliesthe existence of crude or inefficient functional adaptations     

Structural investigation of Klebsiella serotype K70 polysaccharide

By using the techniques of methylation analysis, uronic acid degradation, partial hydrolysis, and periodate oxidation, the structure of the capsular polysaccharide from Klebsiella serotype K70 has been investigated. Nuclear magnetic resonance was used extensively to characterize fragments obtained as a result of the various degradation procedures. The existence of a linear, hexasaccharide repeating unit having a 1-carboxyethylidene group attached to a 2-linked α-l-rhamnosyl residue in every second repeating unit has been demonstrated.