LUBAC synthesizes linear ubiquitin chains via a thioester intermediate

The linear ubiquitin chain assembly complex (LUBAC) is a RING E3 ligase that regulates immune and inflammatory signalling pathways. Unlike classical RING E3 ligases, LUBAC determines the type of ubiquitin chain being formed, an activity normally associated with the E2 enzyme. We show that the RING-in-between-RING (RBR)-containing region of HOIP-the catalytic subunit of LUBAC-is sufficient to generate linear ubiquitin chains. However, this activity is inhibited by the N-terminal portion of the molecule, an inhibition that is released upon complex formation with HOIL-1L or SHARPIN. Furthermore, we demonstrate that HOIP transfers ubiquitin to the substrate through a thioester intermediate formed by a conserved cysteine in the RING2 domain, supporting the notion that RBR ligases act as RING/HECT hybrids.     

SecA: a tale of two protomers

Bacteria, Archaea and Eukaryotes have evolved a plethora of mechanisms to translocate proteins across their various membranes. The bacterial Sec pathway is ubiquitous and essential for cell viability and is used by most proteins destined for the inner membrane, the periplasm or beyond. In bacteria, Sec system components include the heterotrimers SecY/SecE/SecG and SecD/SecF/YajC and the peripherally associated ATPase motor SecA. SecA in solution is mainly dimeric. Unexpectedly, structures of SecA dimers from different or even the same bacterium do not have a consistent dimerization interface. Analysis of the functional assembled translocase complexes blurs the picture even further as the functional quaternary state of the SecYEG channel is also disputed. Several experimental approaches tried to define the oligomeric state of SecA during preprotein ‘pushing’ through SecYEG. One high‐resolution SecA–SecYEG complex has been visualized. This snapshot might be a step closer to the actual translocating machinery. Nevertheless, because of the use of detergent, the true quartenary state of the translocase might have been disturbed. Hence, even after this and other studies, several issues remain puzzling. New approaches must be combined with current tools to gain insight into the functionally relevant quartenary states of SecA and SecYEG during preprotein translocation.     

α7 Nicotinic Acetylcholine Receptor-Specific Antibody Induces Inflammation and Amyloid β42 Accumulation in the Mouse Brain to Impair Memory

Nicotinic acetylcholine receptors (nAChRs) expressed in the brain are involved in regulating cognitive functions, as well as inflammatory reactions. Their density is decreased upon Alzheimer disease accompanied by accumulation of β-amyloid (Aβ₄₂), memory deficit and neuroinflammation. Previously we found that α7 nAChR-specific antibody induced pro-inflammatory interleukin-6 production in U373 glioblastoma cells and that such antibodies were present in the blood of humans. We raised a hypothesis that α7 nAChR-specific antibody can cause neuroinflammation when penetrating the brain. To test this, C57Bl/6 mice were either immunized with extracellular domain of α7 nAChR subunit α7(1-208) or injected with bacterial lipopolysaccharide (LPS) for 5 months. We studied their behavior and the presence of α3, α4, α7, β2 and β4 nAChR subunits, Aβ₄₀ and Aβ₄₂ and activated astrocytes in the brain by sandwich ELISA and confocal microscopy. It was found that either LPS injections or immunizations with α7(1-208) resulted in region-specific decrease of α7 and α4β2 and increase of α3β4 nAChRs, accumulation of Aβ₄₂ and activated astrocytes in the brain of mice and worsening of their episodic memory. Intravenously transferred α7 nAChR-specific-antibodies penetrated the brain parenchyma of mice pre-injected with LPS. Our data demonstrate that (1) neuroinflammation is sufficient to provoke the decrease of α7 and α4β2 nAChRs, Aβ₄₂ accumulation and memory impairment in mice and (2) α7(1-208) nAChR-specific antibodies can cause inflammation within the brain resulting in the symptoms typical for Alzheimer disease.     

Fungal–bacterial interactions and their relevance in health

Cross‐kingdom interactions between bacteria and fungi are a common occurrence in the environment. Recent studies have identified various types of interactions that either can take the form of a synergistic relationship or can result in an antagonistic interplay with the subsequent destruction or inhibition of growth of bacteria, fungi or both. This cross‐kingdom communication is of particular significance in human health and disease, as bacteria and fungi commonly colonize various human surfaces and their interactions can at times alter the outcome of invasive infections. Moreover, mixed infections from both bacteria and fungi are relatively common among critically ill patients and individuals with weak immune responses. The purpose of this review is to summarize our knowledge on the type of interactions between bacteria and fungi and their relevance in human infections.     

BDNF serum concentrations in first psychotic episode drug-naïve schizophrenic patients: Associations with personality and BDNF Val66Met polymorphism

AimsTo investigate the relationship among brain derived neurotrophic factor (BDNF) serum concentrations, BDNF Val66Met polymorphism and personality profile in drug-naïve schizophrenic patients with first-episode psychosis (FEP) and healthy participants.Main methodsThis cross-sectional study included fifty FEP patients and fifty healthy participants who served as controls. To study their personality profile the standardized Greek version of the Alternative Five-Factor Zuckerman–Kuhlman Personality Questionnaire (ZKPQ) was administered. Serum BDNF levels were measured and genotyping of BDNF Val66Met polymorphism was performed in patients and healthy subjects.Key findingsFEP patients presented lower BDNF serum concentrations (P = 0.002) and higher scores in ZKPQ Neuroticism (P = 0.001) and Aggression–Hostility (P = 0.002) scales while lower scores in the ZKPQ Sociability scale (P < 0.001) than healthy participants. Multivariate analysis revealed that the odds of being assessed with FEP were 0.4 times lower in those with higher BDNF values (P < 0.001) and 1.8 times greater in those with higher Neuroticism scores (P < 0.001). There were no significant differences with respect to the Val66Met polymorphism between patients and healthy participants.SignificanceReduced BDNF serum concentrations along with higher Neuroticism scores might be associated with FEP. A complex interplay between BDNF serum concentrations, personality traits, BDNF Val66Met polymorphism, and psychotic symptomatology has been arisen but further investigation is needed to better clarify the observed associations.