Inflammatory diseases: is ubiquitinated NEMO at the hub?

Many patients with Crohn's disease carry mutations in NOD2, a molecule that can both activate and attenuate the pro-inflammatory effects of NF-kappa B. Recent studies implicate NOD2-induced ubiquitination of the NF-kappa B regulator NEMO as a potential means of manipulating the NF-kappa B signal.     

Cdc45: the missing RecJ ortholog in eukaryotes?

DNA replication is one of the most ancient of cellular processes and functional similarities among its molecular machinery are apparent across all cellular life. Cdc45 is one of the essential components of the eukaryotic replication fork and is required for the initiation and elongation of DNA replication, but its molecular function is currently unknown. In order to trace its evolutionary history and to identify functional domains, we embarked on a computational sequence analysis of the Cdc45 protein family. Our findings reveal eukaryotic Cdc45 and prokaryotic RecJ to possess a common ancestry and Cdc45 to contain a catalytic site within a predicted exonuclease domain. The likely orthology between Cdc45 and RecJ reveals new lines of enquiry into DNA replication mechanisms in eukaryotes.     

Cdc48 (p97): a ‘molecular gearbox’ in the ubiquitin pathway?

Cdc48 (p97), a conserved chaperone-like ATPase of eukaryotic cells, has attracted attention recently because of its wide range of cellular functions. Cdc48 is intimately linked to the ubiquitin pathway because its primary action is to segregate ubiquitinated substrates from unmodified partners. This 'segregase' activity is crucial for certain proteasomal degradation pathways and for some nonproteolytic functions of ubiquitin. Cdc48 associates not only with different 'substrate-recruiting cofactors' but also with distinct 'substrate-processing cofactors'. The latter proteins control the degree of ubiquitination of bound substrates by shifting the polyubiquitination reaction into 'forward', 'neutral' or 'reverse'. We discuss how Cdc48 might use this 'gearbox activity' to control protein fate and propose a similar mode of action for the 19S cap of the proteasome.     

Antigens and autophagy: the path less travelled?

The Epstein-Barr virus (EBV)-coded nuclear antigen (EBNA) 1, a latent cycle protein endogenously expressed in EBV-transformed B lymphoblastoid cell lines (LCLs), is reported to be processed for CD4(+) T cell recognition by an intracellular route involving antigen delivery to the endosome/lyosome (MHC class II loading) compartment via macroautophagy. In contrast we find that, in the same cell type, two other virus-coded nuclear proteins of the latent cycle, EBNA2 and EBNA3C, are processed by a different route that is unaffected by autophagy inhibition. This involves the intercellular transfer of an antigenic moiety, detectable in cell-free culture supernatants, and its uptake and processing as exogenous antigen by neighboring cells. The process is cumulative and leads over several days of LCL culture to high levels of CD4+ T cell epitope display. The presentation of certain EBV lytic cycle proteins to CD4+ T cells has also recently been found to involve a similar intercellular antigen transfer. It becomes important to know why, even in the same cell type, some antigens but not others appear to access the MHC class II presentation pathway by autophagy.     

Are islands the end of the colonization road?

Ecologists have, up to now, widely regarded colonization of islands from continents as a one-way journey, mainly because of widely accepted assertions that less diverse island communities are easier to invade. However, continents present large targets and island species should be capable of making the reverse journey, considering they are the direct descendants of successful colonists and provided that they have not lost their dispersal abilities. Recent mapping of geography onto molecular phylogenies has revealed several cases of 'reverse colonization' (from islands to continents). We suggest this phenomenon warrants closer attention in ecology and biogeography. Assessing its significance will contribute to understanding the role of dispersal and establishment in biogeographic distributions and the assembly of natural biotas.     

Insensitivity to road salt: an advantage for the American bullfrog?

The health of freshwater ecosystems is negatively affected by a multitude of pollutants. In northern latitudes, road deicing agents enter nearby ponds and waterways elevating chloride concentrations in winter and spring. Few studies have examined how amphibians respond to road salt contamination and no study has focused on the response of an invasive amphibian. We examined the effects of NaCl, the most commonly used deicing agent, on the embryos and tadpoles of the American bullfrog, Lithobates catesbeianus, a species that is invasive in many regions around the world. In the first experiment, we exposed L. catesbeianus embryos to ecologically relevant levels of chloride for 60 days. The second experiment examined the indirect consequences of chloride contamination by exposing L. catesbeianus tadpoles to dragonfly larvae. Lithobates catesbeianus did not experience reduced survival, growth, or ability to evade predation in elevated chloride concentrations compared to controls. The lack of a response by L. catesbeianus suggests that its population growth will not be negatively impacted by road salt contamination. This result may be good news for L. catesbeianus, but raises concern for sympatric amphibians that have to contend with negative impacts of both chloride contamination and non-native L. catesbeianus.     

Cdc37: a protein kinase chaperone?

The activity of most protein kinases is highly regulated, typically via phosphorylation and/or subunit association. However, the folding of protein kinases into an active state or a form capable of activation is now emerging as another important step through which they can be regulated. The 50-kDa protein Cdc37 and the associated heat-shock protein Hsp90 have been found to bind to, and be required for the activity of, diverse protein kinases, including Cdk4, v-Src, Raf and SEVENLESS. Together, Cdc37 and Hsp90 may act as a general chaperone for protein kinases, in particular those involved in signal-transduction pathways and cell-cycle control.     

Effects of road salts on the composition of seasonal pond communities: can the use of road salts enhance mosquito recruitment?

Road deicing agents can enter nearby wetlands and alter the composition of aquatic communities by directly eliminating salt-intolerant species and modifying ecological interactions between tolerant species. We conducted field experiments to examine the sensitivity of taxa that inhabit seasonal wetlands and to determine whether salt contamination could increase the production of ovipositing insects. In two outdoor mesocosm experiments, cladocerans and copepods rarely survived concentrations of commercial road salt >1,200 mg L⁻¹, while wood frog eggs and hatchlings (Lithobates sylvaticus) were not strongly impacted until concentrations exceeded 4,500 mg L⁻¹. Shore flies (Ephydridae), mosquitoes (Culex restuans; Anopheles punctipennis) and midge larvae (Chironomidae) were more salt tolerant than macrozooplankton. These taxa tended to be absent or relatively rare in experimental mesocosms with low salinities, but abundant in mesocosms with intermediate to high salinities. We conducted two additional experiments to examine whether adult choice of oviposition sites may in part explain the rarity of Cx. restuans in pools with low salinity. These revealed that Cx. restuans reduced oviposition rates in water-filled containers with cladocerans, and reduced clutch size in the presence of Lithobates larvae. However, salt concentration per se did not influence the propensity of Cx. restuans to oviposit. Collectively, our results suggest that aquatic habitats that are biologically compromised by deicing agents favor salt-tolerant insects, and that the use of road salts could increase the production of adult mosquitoes that are pests and vectors of disease.     

SGLT2 inhibitors and AMPK: The road to cellular housekeeping?

Sodium-glucose co-transporter-2 (SGLT2) inhibitors, known as Gliflozins, are a class of Glucose-lowering drugs in adults with type 2 diabetes (T2D) that induce glucosuria by blocking SGLT2 co-transporters in the proximal tubules. Several lines of evidence suggest that SGLT2 inhibitors regulate multiple mechanisms associated with the regulation of varying cellular pathways. The 5′-adenosine monophosphate-activated protein kinase (AMPK) pathway plays an important role in metabolic homeostasis by influencing cellular processes. Recently, it has been shown that SGLT2 inhibitors can affect the AMPK pathway in differing physiological and pathological ways, resulting in kidney, intestinal, cardiovascular, and liver protective effects. Additionally, they have therapeutic effects on nonalcoholic fatty liver disease and diabetes mellitus-associated complications. In this review, we summarize the results of studies of AMPK-associated therapeutic effects of SGLT2 inhibitors in different organelle functions.     

The complex of cytochrome c and cytochrome c peroxidase: the end of the road?

Cytochrome c (Cc) and cytochrome c peroxidase (CcP) form a physiological complex in the inter-membrane space of yeast mitochondria, where CcP reduces hydrogen peroxide to water using the electrons provided by ferrous Cc. The Cc-CcP system has been a popular choice of study of interprotein biological electron transfer (ET) and in understanding dynamics within a protein-protein complex. In this review we have charted seven decades of research beginning with the discovery of CcP and leading to the latest functional and structural work, which has clarified the mechanism of the intermolecular ET, addressed the putative functional role of a low-affinity binding site, and identified lowly-populated intermediates on the energy landscape of complex formation. Despite the remarkable attention bestowed on this complex, a number of outstanding issues remain to be settled on the way to a complete understanding of Cc-CcP interaction.     

Stem cell therapy for insulin-dependent diabetes: Are we still on the road?

In insulin-dependent diabetes, the islet β cells do not produce enough insulin and the patients must receive exogenous insulin to control blood sugar. However, there are still many deficiencies in exogenous insulin supplementation. Therefore, the replacement of destroyed functional β cells with insulin-secreting cells derived from functional stem cells is a good idea as a new therapeutic idea. This review introduces the development schedule of mouse and human embryonic islets. The differences between mouse and human pancreas embryo development were also listed. Accordingly to the different sources of stem cells, the important research achievements on the differentiation of insulin-secreting β cells of stem cells and the current research status of stem cell therapy for diabetes were reviewed. Stem cell replacement therapy is a promising treatment for diabetes, caused by defective insulin secretion, but there are still many problems to be solved, such as the biosafety and reliability of treatment, the emergence of tumors during treatment, untargeted differentiation and autoimmunity, etc. Therefore, further understanding of stem cell therapy for insulin is needed.     

Molecular systems biology at the crossroads: to know less about more,or to know more about less?

Systems biology is a rapidly evolving discipline that endeavours to understand the detailed coordinated workings of entire organisms, with the ultimate goal to detect differences between health and disease, or to understand how cells or entire organisms react to the environment. The editorial provides a critical evaluation of what molecular systems analysis can and cannot accomplish with existing methodologies, and how systems biology needs to merge with reductionism to yield a more comprehensive and mechanistically insightful model of a cell or organism.