Regulation of Parkin-dependent mitophagy by Bcl-2-associated athanogene (BAG) family members.
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ABSTRACT:
SUBMITTER: Kapadia M
PROVIDER: S-EPMC8067924 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:As pathogenic Parkin mutations result in the defective clearance of damaged mitochondria, Parkin-dependent mitophagy is thought to be protective against the dopaminergic neurodegeneration observed in Parkinson's disease. Recent studies, however, have demonstrated that Parkin can promote cell death in the context of severe mitochondrial damage by degrading the pro-survival Bcl-2 family member, Mcl-1. Therefore, Parkin may act as a 'switch' that can shift the balance between protective or pro-death pathways depending on the degree of mitochondrial damage. Here, we report that the Parkin interacting protein, Bcl-2-associated athanogene 5 (BAG5), impairs mitophagy by suppressing Parkin recruitment to damaged mitochondria and reducing the movement of damaged mitochondria into the lysosomes. BAG5 also enhanced Parkin-mediated Mcl-1 degradation and cell death following severe mitochondrial insult. These results suggest that BAG5 may regulate the bi-modal activity of Parkin, promoting cell death by suppressing Parkin-dependent mitophagy and enhancing Parkin-mediated Mcl-1 degradation.
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Project description:BCL-2-associated athanogene-1 (BAG-1) is expressed by osteoblast-lineage cells; early embryonic lethality in Bag-1 null mice, however, has limited the investigation of BAG-1 function in osteoblast development. In the present study, bone morphogenetic protein-2/BMP-2-directed osteogenic differentiation of bone marrow stromal cells (BMSCs) of Bag-1(+/-) (heterozygous) female mice was decreased significantly. Genes crucial for osteogenic differentiation, bone matrix formation and mineralisation were expressed at significantly lower levels in cultures of Bag-1(+/-) BMSCs supplemented with BMP-2, while genes with roles in inhibition of BMP-2-directed osteoblastogenesis were significantly upregulated. 17-β-estradiol (E2) enhanced responsiveness of BMSCs of wild-type and Bag-1(+/-) mice to BMP-2, and promoted robust BMP-2-stimulated osteogenic differentiation of BMSCs. BAG-1 can modulate cellular responses to E2 by regulating the establishment of functional estrogen receptors (ERs), crucially, via its interaction with heat shock proteins (HSC70/HSP70). Inhibition of BAG-1 binding to HSC70 by the small-molecule chemical inhibitor, Thioflavin-S, and a short peptide derived from the C-terminal BAG domain, which mediates binding with the ATPase domain of HSC70, resulted in significant downregulation of E2/ER-facilitated BMP-2-directed osteogenic differentiation of BMSCs. These studies demonstrate for the first time the significance of BAG-1-mediated protein-protein interactions, specifically, BAG-1-regulated activation of ER by HSC70, in modulation of E2-facilitated BMP-2-directed osteoblast development.
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Project description:Programmed cell death (PCD) is a genetically controlled process for the selective removal of damaged cells. Though understanding about plant PCD has improved over years, the mechanisms are yet to be fully deciphered. Among the several molecular players of PCD in plants, B cell lymphoma 2 (Bcl-2)-associated athanogene (BAG) family of co-chaperones are evolutionary conserved and regulate cell death, growth and development. In this study, we performed a genome-wide in silico analysis of the MusaBAG gene family in a globally important fruit crop banana. Thirteen MusaBAG genes were identified, out of which MusaBAG1, 7 and 8 genes were found to have multiple copies. MusaBAG genes were distributed on seven out of 11 chromosomes in banana. Except for one paralog of MusaBAG8 all the other 12 proteins have characteristic BAG domain. MusaBAG1, 2 and 4 have an additional ubiquitin-like domain whereas MusaBAG5-8 have a calmodulin binding motif. Most of the MusaBAG proteins were predicted to be localized in the nucleus and mitochondria or chloroplast. The in silico cis-regulatory element analysis suggested regulation associated with photoperiodic control, abiotic and biotic stress. The phylogenetic analysis revealed 2 major clusters. Digital gene expression analysis and quantitative real-time RT-PCR depicted the differential expression pattern of MusaBAG genes under abiotic and biotic stress conditions. Further studies are warranted to uncover the role of each of these proteins in growth, PCD and stress responses so as to explore them as candidate genes for engineering transgenic banana plants with improved agronomic traits.
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Project description:Bcl-2-associated athanogene (BAG), a group of proteins evolutionarily conserved and functioned as co-chaperones in plants and animals, is involved in various cell activities and diverse physiological processes. However, the biological functions of this gene family in rice are largely unknown. In this study, we identified a total of six BAG members in rice. These genes were classified into two groups, OsBAG1, -2, -3, and -4 are in group I with a conserved ubiquitin-like structure and OsBAG5 and -6 are in group Ⅱ with a calmodulin-binding domain, in addition to a common BAG domain. The BAG genes exhibited diverse expression patterns, with OsBAG4 showing the highest expression level, followed by OsBAG1 and OsBAG3, and OsBAG6 preferentially expressed in the panicle, endosperm, and calli. The co-expression analysis and the hierarchical cluster analysis indicated that the OsBAG1 and OsBAG3 were co-expressed with primary cell wall-biosynthesizing genes, OsBAG4 was co-expressed with phytohormone and transcriptional factors, and OsBAG6 was co-expressed with disease and shock-associated genes. β-glucuronidase (GUS) staining further indicated that OsBAG3 is mainly involved in primary young tissues under both primary and secondary growth. In addition, the expression of the BAG genes under brown planthopper (BPH) feeding, N, P, and K deficiency, heat, drought and plant hormones treatments was investigated. Our results clearly showed that OsBAGs are multifunctional molecules as inferred by their protein structures, subcellular localizations, and expression profiles. BAGs in group I are mainly involved in plant development, whereas BAGs in group II are reactive in gene regulations and stress responses. Our results provide a solid basis for the further elucidation of the biological functions of plant BAG genes.
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Project description:B-cell lymphoma2 (Bcl-2)-associated athanogene (BAG) family proteins are evolutionary conserved across all eukaryotes. These proteins interact with HSP70/HSC70 and function as co-chaperones during stress response and developmental pathways. Compared to the animal counterpart, the BAG proteins in plants are much less studied and primarily Arabidopsis BAG proteins have been identified and characterized for their role in programmed cell death, homeostasis, growth and development, abiotic and biotic stress response. Here, we have identified BAG protein family (SlBAGs) in tomato, an economically important and a model fruit crop using genome-wide scanning. We have performed phylogenetic analysis, genes architecture assessment, chromosomal location and in silico promoter analysis. Our data suggest that SlBAGs show differential tissue specific expression pattern during plant development particularly fruit development and ripening. Furthermore, we reported that expression of SlBAGs is modulated during abiotic stresses and is regulated by stress hormones ABA and ethylene. In planta subcellular localization reveals their diverse subcellular localization, and many members are localized in nucleus and cytoplasm. Like previous reports, our protein-protein interaction network and yeast two-hybrid analysis uncover that SlBAGs interact with HSP70. The current study provides insights into role of SlBAGs in plant development particualry fruit ripening and abiotic stress response.
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Project description:The Bcl-2-associated athanogene (BAG) proteins are a family of multi-functional group of co-chaperones regulators, modulating diverse processes from plant growth and development to stress response. Here, 10 members of SlBAG gene family were identified based on the available tomato (Solanum lycopersicum) genomic information and named as SlBAG1-10 according to their chromosomal location. All SlBAG proteins harbor a characteristic BAG domain, categorized into two groups, and SlBAG4, SlBAG7, and SlBAG9 of group I contain a plant-specific isoleucine glutamine (IQ) calmodulin-binding motif located in the N terminus. The quantitative real-time PCR expression analysis revealed that these SlBAG genes had organ-specific expression patterns and most SlBAG genes were differentially expressed in multiple abiotic stresses including drought, salt, high temperature, cold, and cadmium stress as well as abscisic acid and H2O2. In addition, heterologous overexpression of SlBAG9 increased the sensitivity of Arabidopsis to drought, salt, and ABA during seed germination and seedling growth. The decreased tolerance may be due to the downregulation of stress-related genes expression and severe oxidative stress. The expression levels of some stress and ABA-related genes, such as ABI3, RD29A, DREB2A, and P5CS1, were significantly inhibited by SlBAG9 overexpression under osmotic stress. Meanwhile, the overexpression of SlBAG9 inhibited the expression of FSD1 and CAT1 under stress conditions and the decreased levels of superoxide dismutase and catalase enzyme activities were detected accompanying the trends in the expression of both genes, which resulted in H2O2 accumulation and lipid peroxidation. Taken together, these findings lay a foundation for the future study of the biological function of SlBAG genes in tomato.
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Project description:Mitochondria can undergo autophagic elimination for differing reasons, e.g. as part of a cell-wide macroautophagic response, as part of mitochondrial turnover during metabolic remodeling, or in the case of selective mitophagic destruction of dysfunctional mitochondria, during mitochondrial quality control. Multiple mechanistically distinct pathways converge upon, and activate, mitochondrial autophagy. Here, the evidence supporting a role for the prototypical mitochondrial quality control pathway, PINK1-Parkin mediated mitophagy, in cardiac homeostasis and heart disease is reviewed. Contrary to popular wisdom based on findings from non-cardiac systems, current data do not support a major role for Parkin-mediated mitophagy as a mechanism for constitutive mitochondrial housekeeping, and instead suggest that this pathway primarily functions in adult hearts as an inducible cardiac stress-response mechanism. Recent findings have also uncovered an unsuspected role for Parkin-mediated mitochondrial turnover in the normal perinatal transformation of myocardial metabolism.
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