BAG3: a multifaceted protein that regulates major cell pathways

Bcl2-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that interacts with the ATPase domain of the heat shock protein (Hsp) 70 through BAG domain (110–124 amino acids). BAG3 is the only member of the family to be induced by stressful stimuli, mainly through the activity of heat shock factor 1 on bag3 gene promoter. In addition to the BAG domain, BAG3 contains also a WW domain and a proline-rich (PXXP) repeat, that mediate binding to partners different from Hsp70. These multifaceted interactions underlie BAG3 ability to modulate major biological processes, that is, apoptosis, development, cytoskeleton organization and autophagy, thereby mediating cell adaptive responses to stressful stimuli. In normal cells, BAG3 is constitutively present in a very few cell types, including cardiomyocytes and skeletal muscle cells, in which the protein appears to contribute to cell resistance to mechanical stress. A growing body of evidence indicate that BAG3 is instead expressed in several tumor types. In different tumor contexts, BAG3 protein was reported to sustain cell survival, resistance to therapy, and/or motility and metastatization. In some tumor types, down-modulation of BAG3 levels was shown, as a proof-of-principle, to inhibit neoplastic cell growth in animal models. This review attempts to outline the emerging mechanisms that can underlie some of the biological activities of the protein, focusing on implications in tumor progression

When supply does not meet demand-ER stress and plant programmed cell death

The endoplasmic reticulum (ER) is the central organelle in the eukaryotic secretory pathway. The ER functions in protein synthesis and maturation and is crucial for proper maintenance of cellular homeostasis and adaptation to adverse environments. Acting as a cellular sentinel, the ER is exquisitely sensitive to changing environments principally via the ER quality control machinery. When perturbed, ER-stress triggers a tightly regulated and highly conserved, signal transduction pathway known as the unfolded protein response (UPR) that prevents the dangerous accumulation of unfolded/misfolded proteins. In situations where excessive UPR activity surpasses threshold levels, cells deteriorate and eventually trigger programmed cell death (PCD) as a way for the organism to cope with dysfunctional or toxic signals. The programmed cell death that results from excessive ER stress in mammalian systems contributes to several important diseases including hypoxia, neurodegeneration, and diabetes. Importantly, hallmark features and markers of cell death that are associated with ER stress in mammals are also found in plants. In particular, there is a common, conserved set of chaperones that modulate ER cell death signaling. Here we review the elements of plant cell death responses to ER stress and note that an increasing number of plant-pathogen interactions are being identified in which the host ER is targeted by plant pathogens to establish compatibility.Peer reviewedEntomology and Plant Patholog

Arabidopsis B-cell lymphoma2 (Bcl-2)-associated athanogene 7 (BAG7)-mediated heat tolerance requires translocation, sumoylation and binding to WRKY29

To cope with stress and increased accumulation of misfolded proteins, plants and animals use a survival pathway known as the unfolded protein response (UPR) that signals between the endoplasmic reticulum (ER) and the nucleus to maintain cell homeostasis via proper folding of proteins. B-cell lymphoma2 (Bcl-2)-associated athanogene (BAG) proteins are an evolutionarily conserved family of co-chaperones that are linked to disease states in mammals and responses to environmental stimuli (biotic and abiotic) in plants. Molecular and physiological techniques were used to functionally characterize a newly identified branch of the UPR initiated by the ER-localized co-chaperone from Arabidopsis thaliana, AtBAG7. AtBAG7 has functional roles in both the ER and the nucleus. Upon heat stress, AtBAG7 is sumoylated, proteolytically processed and translocated from the ER to the nucleus, where interaction with the WRKY29 transcription factor occurs. Sumoylation and translocation are required for the AtBAG7–WRKY29 interaction and subsequent stress tolerance. In the ER, AtBAG7 interacts with the ER-localized transcription factor, AtbZIP28, and established UPR regulator, the AtBiP2 chaperone. The results indicate that AtBAG7 plays a central regulatory role in the heat-induced UPR pathway