The role of fibrinogen glycation in ATTR: evidence for chaperone activity loss in disease.

Transthyretin amyloidosis (ATTR) belongs to a class of disorders caused by protein misfolding and aggregation. ATTR is a disabling disorder of autosomal dominant trait, where transthyretin (TTR) forms amyloid deposits in different organs, causing dysfunction of the peripheral nervous system. We previously discovered that amyloid fibrils from ATTR patients are glycated by methylglyoxal. Even though no consensus has been reached about the actual role of methylglyoxal-derived advanced glycation end-products in amyloid diseases, evidence collected so far points to a role for protein glycation in conformational abnormalities, being ubiquitously found in amyloid deposits in Alzheimer's disease, dialysis-related amyloidosis and Parkinson's diseases. Human fibrinogen, an extracellular chaperone, was reported to specifically interact with a wide spectrum of stressed proteins and suppress their aggregation, being an interacting protein with TTR. Fibrinogen is differentially glycated in ATTR, leading to its chaperone activity loss. Here we show the existence of a proteostasis imbalance in ATTR linked to fibrinogen glycation by methylglyoxal.

Breaking through the stress barrier: the role of BolA in Gram-negative survival.

The morphogene bolA plays a significant role in the adaptation of Escherichia coli to general stresses. In general, bacteria can thrive and persist under harsh conditions, counteracting external stresses by using varied mechanisms, including biofilm formation, changes in cell shape, size and protein content, together with alterations in the cell wall structure, thickness and permeability. In E. coli, an increased expression of bolA occurs mainly under stress challenges and when bacterial morphology changes from rod-like to spherical. Moreover, BolA is able to induce biofilm formation and changes in the outer membrane, making it less permeable to harmful agents. Although there has been substantial progress in the description of BolA activity, its role on global cell physiology is still incomplete. Proteins with strong homology to BolA have been found in most living organisms, in many cases also exerting a regulatory role. In this review we summarize current knowledge on the role of BolA, mainly in E. coli, and discuss its implication in global regulation in relation to stress.

Characterization of the BolA homolog IbaG: a new gene involved in acid resistance.

BolA protein homologs are widely distributed in nature. In this report, we have studied for the first time YrbA, the only BolA homolog present in Escherichia coli, which we have renamed ibaG. We have constructed single and multiple ibaG mutants, and overexpressed ibaG in wildtype strains, in order to characterize this gene. The ibaG phenotypes are different from the bolA-associated round morphologies or growth profiles. Interestingly, ibaG and bolA single- and double-deletion mutants grow faster and have higher viabilities in rich media, whereas the overexpressed strains are significantly growth impaired. However, the mutant strains have lower viabilities than the wild type in the late stationary phase, indicating that both bolA and ibaG are important for survival in difficult growth conditions. bolA, as a transcription factor, binds to some promoters, but ibaG does not interact with the same DNA regions. We have determined that ibaG is transcribed in an operon with the murA gene, involved in the synthesis of peptidoglycan precursors. ibaG was also seen to change its mRNA expression pattern in response to acidic stress. ibaG may thus represent a new gene involved in cell resistance against acid stress.

BolA affects cell growth, and binds to the promoters of penicillin-binding proteins 5 and 6 and regulates their expression.

The gene bolA was discovered in the 80's, but unraveling its function in the cell has proven to be a complex task. The BolA protein has pleiotropic effects over cell physiology, altering growth and morphology, inducing biofilm formation, and regulating the balance of several membrane proteins. Recently, BolA was shown to be a transcription factor by repressing the expression of the mreB gene. The present report shows that BolA is a transcriptional regulator of the dacA and dacC genes, thus regulating both DD-carboxypeptidases PBP5 and PBP6 and thereby demonstrating the versatility of BolA as a cellular regulator. In this work, we also demonstrate that reduction of cell growth and survival can be connected to the overexpression of the bolA gene in different E. coli backgrounds, particularly in the exponential growth phase. The most interesting finding is that overproduction of BolA affects bacterial growth differently depending on whether the cells were inoculated directly from a plate culture or from an overnight batch culture. This strengthens the idea that BolA can be engaged in the coordination of genes that adapt the cell physiology in order to enhance cell adaptation and survival under stress conditions.