Role of BAG5 in Protein Quality Control: Double-Edged Sword?

Abstract

Cardiovascular disorder is the major health burden and cause of death among individuals worldwide. As the cardiomyocytes lack the ability for self-renewal, it is utmost necessary to surveil the protein quality in the cells. The Bcl-2 associated anthanogene protein (BAG) family and molecular chaperones (HSP70, HSP90) actively participate in maintaining cellular protein quality control (PQC) to limit cellular dysfunction in the cells. The BAG family contains a unique BAG domain which facilitates their interaction with the ATPase domain of the heat shock protein 70 (HSP70) to assist in protein folding. Among the BAG family members (BAG1-6), BAG5 protein is unique since it has five domains in tandem, and the binding of BD5 induces certain conformational changes in the nucleotide-binding domain (NBD) of HSP70 such that it loses its affinity for binding to ADP and results in enhanced protein refolding activity of HSP70. In this review, we shall describe the role of BAG5 in modulating mitophagy, endoplasmic stress, and cellular viability. Also, we have highlighted the interaction of BAG5 with other proteins, including PINK, DJ-1, CHIP, and their role in cellular PQC. Apart from this, we have described the role of BAG5 in cellular metabolism and aging.

Molecular Landscape of Tourette’s Disorder

“…Ubiquitination marks proteins for proteasome-dependent degradation, while sumoylation is not used to tag proteins for degradation but modifies proteins involved in many cellular processes including gene expression, chromatin structure, signal transduction, DNA damage response and cell cycle progression. Molecular chaperone proteins such as BAG5 and HSP90AA1 —that has very many interactions in the landscape, such as forming a complex with the adaptor protein ST13 —play an important role in maintaining a protein’s native folding and function, which protects against the buildup of misfolded proteins [ 97 ]. When misfolded proteins interact with chaperones (which cannot be refolded), they can be shuttled for ubiquitin-dependent proteasome degradation.…”

“Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction”

“…Indeed, this integrative approach showed that BAG5, detected by RNA-seq, appears to strictly interact with TRiC complex. BAG5 is involved in endoplasmic reticulum stress regulation and unfolded protein response activation [60]. In particular, BAG5 interacts with heatshock proteins acting as a cochaperone in protein folding [72].…”

“…S5E), is now complemented by BAG5, involved in endoplasmic reticulum stress regulation and unfolded protein response activation [59]. In fact, it has been described that the protein BAG5 is a cochaperone involved in protein folding [60].…”

Akt Is Controlled by Bag5 through a Monoubiquitination to Polyubiquitination Switch

“…We found that different constructs of BAG5 reduced the expression of cotransfected Akt (see total cell lysates, TCL, in Figure 1F). Thus, considering that BAG proteins are recognized as chaperone regulators and BAG5, in particular, regulates protein stability via Hsp70 and modulates the activity of E3 ligases and autophagosomerelated proteins [28,[33][34][35], we wanted to evaluate the role of BAG5 as a potential modulator of Akt stability. In order to start exploring the mechanism by which BAG5 promoted Akt degradation, we assessed whether the kinase was targeted to ubiquitination via BAG5.…”

“…Rac and Erk protein levels, used as controls, did not change in response to ADC regardless of changes in the expression of BAG5, either by overexpression or knockdown (Figure 2D,E). We then postulated that the effect of BAG5 on Akt was mediated by Hsp70, whose activity is known to be regulated by BAG5 [25,33], and which has a documented effect on Akt stability and function [24,37].…”