Evidence for BAG3 modulation of HIV‐1 gene transcription

Abstract

A family of co-chaperone proteins that share the Bcl-2-associated athanogene (BAG) domain are involved in a number of cellular processes, including proliferation and apoptosis. Among these proteins, BAG3 has received increased attention due to its high levels in several disease models and ability to associate with Hsp70 and a number of other molecular partners. BAG3 expression is stimulated during cell response to stressful conditions, such as exposure to high temperature, heavy metals, and certain drugs. Here, we demonstrate that BAG3 expression is elevated upon HIV-1 infection of human lymphocytes and fetal microglial cells. Furthermore, BAG3 protein was detectable in the cytoplasm of reactive astrocytes in HIV-1-associated encephalopathy biopsies, suggesting that induction of BAG3 is part of the host cell response to viral infection. To assess the impact of BAG3 upregulation on HIV-1 gene expression, we performed transcription assays and demonstrated that BAG3 can suppress transcription of the HIV-1 long terminal repeat (LTR) in microglial cells. This activity was mapped to the κB motif of the HIV-1 LTR. Results from in vitro and in vivo binding assays revealed that BAG3 suppresses interaction of the p65 subunit of NF-κB with the κB DNA motif of the LTR. Results from binding and transcriptional assay identified the Cterminus of BAG3 as a potential domain involved in the observed inhibitory effect of BAG3 on p65 activity. These observations reveal a previously unrecognized cell response, that is, an increase in BAG3, elicited by HIV-1 infection, and may provide a new avenue for the suppression of HIV-1 gene expression.

AtBAG7 , an Arabidopsis Bcl-2–associated athanogene, resides in the endoplasmic reticulum and is involved in the unfolded protein response

“…Mammalian BAGs are known cochaperones that are involved in PCD pathways during abiotic and biotic stress responses (41)(42)(43). Although the demonstration of AtBAG7 and BiP interaction via BiFC assays suggests a role for AtBAG7 as a cochaperone for the maintenance of the UPR, further studies were required to confirm this interaction.…”

IKKγ protein is a target of BAG3 regulatory activity in human tumor growth

“…In humans, bag3 is constitutively expressed in myocytes and a few other normal cell types and in several tumors (leukemia and lymphoma, myeloma, and pancreas and thyroid carcinomas) (11,(16)(17)(18)(19)(20). In addition, its expression is induced in different normal cell types (leukocytes and epithelial and glial cells) in response to cell stressors, such as oxidants, high temperature, heavy metals, and HIV-1 infection (15,(21)(22)(23). Interestingly, induction of bag3 in response to stress is under the control of HSF1 (24), a member of the heat shock factor family of transcription factors (25,26) involved in tumor initiation and maintenance (27,28).…”

Deletion of thebisgene results in a marked increase in the production of corticosterone that is associated with thymic atrophy in mice

“…The prosurvival activity of Bis was supported by later studies showing that Bis is overexpressed in several types of cancer and that the downmodulation of Bis sensitizes the apoptosis of tumor cells induced by chemotherapeutic agents and proteasome inhibitors (9,32,38,39). In addition to the prosurvival activity of Bis, its induction under a variety of stresses in vitro as well as in vivo, including hypoxia and viral infections (3,4,25,31,33,40), suggests that Bis might function as an antistress protein to modulate cellular response, thereby protecting cells from unfavorable environmental stresses. Other biological functions in which Bis is involved include the promotion of differentiation as shown in promyelocytes or E19 embryonic stem cells (45), the regulation of motility migration and invasion (20,24,26), and protein quality control via the promotion of autophagy (5,13,16,19).…”