Role of proteasomes in disease

A functional ubiquitin proteasome system is essential for all eukaryotic cells and therefore any alteration to its components has potential pathological consequences. Though the exact underlying mechanism is unclear, an age-related decrease in proteasome activity weakens cellular capacity to remove oxidatively modified proteins and favours the development of neurodegenerative and cardiac diseases. Up-regulation of proteasome activity is characteristic of muscle wasting conditions including sepsis, cachexia and uraemia, but may not be rate limiting. Meanwhile, enhanced presence of immunoproteasomes in aging brain and muscle tissue could reflect a persistent inflammatory defence and anti-stress mechanism, whereas in cancer cells, their down-regulation reflects a means by which to escape immune surveillance. Hence, induction of apoptosis by synthetic proteasome inhibitors is a potential treatment strategy for cancer, whereas for other diseases such as neurodegeneration, the use of proteasome-activating or -modulating compounds could be more effective

Effect of the multicatalytic proteinase (prosome) on translational activity in rabbit reticulocyte lysates

AbstractIn a message-dependent reticulocyte lysate translation system, incorporation of [3H]leucine into acid-insoluble protein is increased following selective removal of the multicatalytic proteinase (MCP) with a monospecific antibody. Re-addition of active proteinase to previously depleted lysates reverses this effect in that the same low levels of translational product are measured as in untreated lysates. Addition of histone-stimulated MCP further depresses the level of protein product. Conversely, lysates supplemented with inactivated MCP retain the higher level of translational activity which is measured after precipitation of the enzyme with antibody. In these lysates, the effect of the antibody on translational activity is inversely correlated with that on hydrolytic activity towards [14C]methylcasein or N-succinyl-Leu-Leu-Val-Tyr-4-methyl-7-coumarylamide, two substrates of the MCP. These results showing that the MCP is capable of modulating translational activity in vitro, suggest an important role of this molecule in the in vivo translational process

Mitigation of Non-CO2 Aviation’s Climate Impact by Changing Cruise Altitudes

Aviation is seeking for ways to reduce its climate impact caused by CO2 emissions and non-CO2 effects. Operational measures which change overall flight altitude have the potential to reduce climate impact of individual effects, comprising CO2 but in particular non-CO2 effects. We study the impact of changes of flight altitude, specifically aircraft flying 2000 feet higher and lower, with a set of global models comprising chemistry-transport, chemistry-climate and general circulation models integrating distinct aviation emission inventories representing such alternative flight altitudes, estimating changes in climate impact of aviation by quantifying radiative forcing and induced temperature change. We find in our sensitivity study that flying lower leads to a reduction of radiative forcing of non-CO2 effects together with slightly increased CO2 emissions and impacts, when cruise speed is not modified. Flying higher increases radiative forcing of non-CO2 effects by about 10%, together with a slight decrease of CO2 emissions and impacts. Overall, flying lower decreases aviation-induced temperature change by about 20%, as a decrease of non-CO2 impacts by about 30% dominates over slightly increasing CO2 impacts assuming a sustained emissions scenario. Those estimates are connected with a large but unquantified uncertainty. To improve the understanding of mechanisms controlling the aviation climate impact, we study the geographical distributions of aviation-induced modifications in the atmosphere, together with changes in global radiative forcing and suggest further efforts in order to reduce long standing uncertainties

Role of S100 proteins in health and disease

The S100 family of proteins contains 25 known members that share a high degree of sequence and structural similarity. However, only a limited number of family members have been characterized in depth, and the roles of other members are likely undervalued. Their importance should not be underestimated however, as S100 family members function to regulate a diverse array of cellular processes including proliferation, differentiation, inflammation, migration and/or invasion, apoptosis, Ca2+ homeostasis, and energy metabolism. Here we detail S100 target protein interactions that underpin the mechanistic basis to their function, and discuss potential intervention strategies targeting S100 proteins in both preclinical and clinical situations

Extracellular, circulating proteasomes and ubiquitin — Incidence and relevance

AbstractThe ubiquitin–proteasome system is the major pathway for intracellular protein degradation and is also deeply involved in the regulation of most basic cellular processes. Its proteolytic core, the 20S proteasome, has found to be attached also to the cell plasma membrane and certain observations are interpreted as to suggest that they may be released into the extracellular medium, e.g. in the alveolar lining fluid, epididymal fluid and possibly during the acrosome reaction. Proteasomes have also been detected in normal human blood plasma and designated circulating proteasomes; these have a comparatively low specific activity, a distinct pattern of subtypes and their exact origin is still enigmatic. In patients suffering from autoimmune diseases, malignant myeloproliferative syndromes, multiple myeloma, acute and chronic lymphatic leukaemia, solid tumour, sepsis or trauma, respectively, the concentration of circulating proteasomes has been found to be elevated, to correlate with the disease state and has even prognostic significance. Similarly, ubiquitin has been discovered as a normal component of human blood and seminal plasma and in ovarian follicular fluid. Increased concentrations were measured in diverse pathological situations, not only in blood plasma but also in cerebrospinal fluid, where it may have neuroprotective effects. As defective spermatozoa are covered with ubiquitin in the epididymal fluid, extracellular ubiquitination is proposed to be a mechanism for quality control in spermatogenesis. Growing evidence exists also for a participation of extracellular proteasomes and ubiquitin in the fertilization process

Can we reliably assess climate mitigation options for air trafficscenarios despite large uncertainties in atmospheric processes?

Air traffic has an increasing influence on climate; therefore identifying mitigation options to reduce the climate impact of aviation becomes more and more important. Aviation influences climate through several climate agents, which show different dependencies on the magnitude and location of emission and the spatial and temporal impacts. Even counteracting effects can occur. Therefore, it is important to analyse all effects with high accuracy to identify mitigation potentials. However, the uncertainties in calculating the climate impact of aviation are partly large (up to a factor of about 2). In this study, we present a methodology, based on a Monte Carlo simulation of an updated non-linear climate-chemistry response model AirClim, to integrate above mentioned uncertainties in the climate assessment of mitigation options. Since mitigation options often represent small changes in emissions, we concentrate on a more generalised approach and use exemplarily different normalised global air traffic inventories to test the methodology. These inventories are identical in total emissions but differ in the spatial emission distribution. We show that using the Monte Carlo simulation and analysing relative differences between scenarios lead to a reliable assessment of mitigation potentials. In a use case we show that the presented methodology can be used to analyse even small differences between scenarios with mean flight altitude variations