BAG3: a multifaceted protein that regulates major cell pathways

Rosati, A; Graziano, V; De Laurenzi, V; Pascale, M; Turco, M C

In some cell types, bag3 expression appears to be developmentally regulated. In the developing central nervous system (CNS) of a rat, there is a transient expression, detectable by immunohistochemistry, of BAG3 in the cerebral cortex and hippocampus, whereas a considerable expression is maintained in the rostral migratory stream and the subventricular zone of the lateral ventricle; there is an abrupt increase of BAG3-positive neurons in the cortex and hippocampus during the first postnatal week, which declines thereafter. Two specific populations of BAG3-positive neurons can be identified in the developing forebrain of a rat. 54 Furthermore, recent results indicated that BAG3 is expressed in neural progenitors and sustains proliferation, mainly in response to FGF2, in those cells. 55 In addition, an early transient expression of BAG3 was observed in midline radial glia in the developing brainstem and spinal cord of a rat. 56 Together, these pieces of evidence indicate a role for BAG3 in the development of both the neuronal and glial components of central nervous system. In agreement with the hypothesis of BAG3 involvement in CNS development, an altered BAG3 expression was observed in the cerebellum of hypothyroid juvenile mice, and was suggested to contribute to impaired development of the hypothyroid brain. Moreover, in rat and human cardiomyocytes, BAG3 protein appears to be expressed during differentiation from cardiomyoblasts and to sustain myogenin expression. 57 These findings indicate an involvement of BAG3 protein in late heart development and are in keeping with the role of BAG3 in the survival and myofibrillar integrity in cardiocytes and, in general, in muscle cells. Indeed, mice with homozygous disruption of bag3 gene develop post birth an early fulminant myopathy 23 and, in humans, a heterozygous p.Pro209Leu mutation in BAG3 protein was recently recognized to be responsible for a severe muscular dystrophy with cardiomyopathy and severe respiratory insufficiency. [57] [58] [59] In one of the three studied families carrying this mutation, an axonal neuropathy was also present. This observation is intriguing in view of the reported localization of a 40 kD form of BAG3 in synaptosomes 11 and of the above discussed role of BAG3 in CNS. Finally, a recent paper reports a role of BAG3 in the development of the hematopoietic system, showing that mice with a targeted disruption of bag3 exhibit a loss of hematopoietic stem cells and defective B-cell development, because of the microenvironmental defect, that is, an alteration in the vascular stem cell niche. 60 The authors observed a defective growth of stromal progenitor cells in colony-forming unit fibroblasts, a defect in sinusoidal endothelium, and the loss of stromal cells expressing CXCL-12 or IL-7 in the bone marrow. 60 The molecular mechanisms underlying those perturbations could, once identified, disclose novel prospects in the understanding of the hematopoietic process. Last but not least, recent evidence indicate that BAG3 is also implicated in regulating the general metabolic state of the organism, as bag3-deficient mice were reported to show significant hypoglycemia, a decrease in triglyceride and cholesterol levels and growth retardation, and died by 3 weeks after birth. 61 Altogether these data show a fundamental role of BAG3 in regulating essential physiological events.