Search results for "PROTEOSTASIS"

Modulation of protein synthesis and degradation maintains proteostasis during yeast growth at different temperatures

2016

To understand how cells regulate each step in the flow of gene expression is one of the most fundamental goals in molecular biology. In this work, we have investigated several protein turnover-related steps in the context of gene expression regulation in response to changes in external temperature in model yeast Saccharomyces cerevisiae. We have found that the regulation of protein homeostasis is stricter than mRNA homeostasis. Although global translation and protein degradation rates are found to increase with temperature, the increase of the catalytic activity of ribosomes is higher than the global translation rate suggesting that yeast cells adapt the amount of translational machinery to…

On the origin of BAG(3) and its consequences for an expansion of BAG3's role in protein homeostasis

2021

The B-cell CLL 2-associated athanogene (BAG) protein family in general and BAG3, in particular, are pivotal elements of cellular protein homeostasis, with BAG3 playing a major role in macroautophagy. In particular, in the contexts of senescence and degeneration, BAG3 has exhibited an essential role often related to its capabilities to organize and remove aggregated proteins. Exciting studies in different species ranging from human, murine, zebrafish, and plant samples have delivered vital insights into BAG3s' (and other BAG proteins') functions and their regulations. However, so far no studies have addressed neither BAG3's evolution nor its phylogenetic position in the BAG family.

The Sigma-1 Receptor at the Crossroad of Proteostasis, Neurodegeneration, and Autophagy.

2020

Neurodegenerative diseases are linked to dysfunctional proteostasis and disturbed autophagy. Here, we discuss how the sigma-1 receptor (Sig-1R) may act at the intersection of this interaction, as loss-of-function mutations of this unique chaperone are associated with defective autophagy and its pharmacological activation induces autophagic activity.

BAG2 Interferes with CHIP-Mediated Ubiquitination of HSP72

2016

The maintenance of cellular proteostasis is dependent on molecular chaperones and protein degradation pathways. Chaperones facilitate protein folding, maturation, and degradation, and the particular fate of a misfolded protein is determined by the interaction of chaperones with co-chaperones. The co-factor CHIP (C-terminus of HSP70-inteacting protein, STUB1) ubiquitinates chaperone substrates and directs proteins to the cellular degradation systems. The activity of CHIP is regulated by two co-chaperones, BAG2 and HSPBP1, which are potent inhibitors of the E3 ubiquitin ligase activity. Here, we examined the functional correlation of HSP72, CHIP, and BAG2, employing human primary fibroblasts.…

Effects of muscular dystrophy, exercise and blocking activin receptor IIB ligands on the unfolded protein response and oxidative stress

2016

Protein homeostasis in cells, proteostasis, is maintained through several integrated processes and pathways and its dysregulation may mediate pathology in many diseases including Duchenne muscular dystrophy (DMD). Oxidative stress, heat shock proteins, endoplasmic reticulum (ER) stress and its response, i.e. unfolded protein response (UPR), play key roles in proteostasis but their involvement in the pathology of DMD are largely unknown. Moreover, exercise and activin receptor IIB blocking are two strategies that may be beneficial to DMD muscle, but studies to examine their effects on these proteostasis pathways are lacking. Therefore, these pathways were examined in the muscle of mdx mice, …

Novel Modulators of Proteostasis: RNAi Screen of Chromosome I in a Heat Stress Paradigm in C. elegans

2018

Proteostasis is of vital importance for cellular function and it is challenged upon exposure to acute or chronic insults during neurodegeneration and aging. The proteostasis network is relevant for the maintenance of proteome integrity and mainly comprises molecular chaperones and two degradation pathways, namely, autophagy and the ubiquitin proteasome system. This network is characterized by an impressive functional interrelation and complexity, and occasionally novel factors are discovered that modulate proteostasis. Here, we present an RNAi screen in C. elegans, which aimed to identify modulators of proteostasis in a heat stress paradigm. The screen comprised genes that are located on ch…

Redox lipidomics to better understand brain aging and function

2019

Human prefrontal cortex (PFC) is a recently evolutionary emerged brain region involved in cognitive functions. Human cognitive abilities decline during aging. Yet the molecular mechanisms that sustain the preservation or deterioration of neurons and PFC functions are unknown. In this review, we focus on the role of lipids in human PFC aging. As the evolution of brain lipid concentrations is particularly accelerated in the human PFC, conferring a specific lipid profile, a brief approach to the lipidome of PFC was consider along with the relationship between lipids and lipoxidative damage, and the role of lipids in human PFC aging. In addition, the specific targets of lipoxidative damage in h…

Role of Hsp70 in Multiple Sclerosis: An Overview

2019

For many years heat shock protein 70 (Hsp70) was considered exclusively an intracellular chaperone contributing to protein proteostasis and in apoptotic pathway block. Lately it has been demonstrated that Hsp70 is actively released in the extracellular environment, thereby promoting the activation of the immune system by stimulating innate and adaptive responses through the activation of APCs. Its expression in the nervous system is induced in a variety of pathological conditions. Emerging evidences displayed that Hsp70 is a critical regulator in normal neural cells. Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) directed against myelin antigens. In thi…

Sprint and Strength Training Modulates Autophagy and Proteostasis in Aging Sprinters

2020

Purpose Exercise and aging may modulate muscle protein homeostasis and autophagy, but few studies examine highly-trained middle-aged or older individuals. This study elucidated the effects of a new long-term training stimulus on markers of muscle autophagy and unfolded protein response (UPR) and on sprint running performance in masters sprinters. Methods Thirty-two male competitive sprinters (aged 40–76 years) were randomly divided into experimental (EX) and control (CTRL) groups. The EX training program was a combination of heavy and explosive strength and sprint exercises aimed at improving sprint performance. Fifteen and thirteen participants completed the 20-week intervention period in …

2020

BAG3, a multifunctional HSP70 co-chaperone and anti-apoptotic protein that interacts with the ATPase domain of HSP70 through its C-terminal BAG domain plays a key physiological role in cellular proteostasis. The HSP70/BAG3 complex determines the levels of a large number of selective client proteins by regulating their turnover via the two major protein degradation pathways, i.e. proteasomal degradation and macroautophagy. On the one hand, BAG3 competes with BAG1 for binding to HSP70, thereby preventing the proteasomal degradation of its client proteins. By functionally interacting with HSP70 and LC3, BAG3 also delivers polyubiquitinated proteins to the autophagy pathway. BAG3 exerts a numbe…