Evidence for BAG3 modulation of HIV-1 gene transcription.
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 kappaB 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-kappaB with the kappaB DNA motif of the LTR. Results from binding and transcriptional assay identified the C-terminus 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.
Rosati
Alessandra
A
Department of Pharmaceutical Sciences (DiFarma), University of Salerno, Salerno, Italy.
Leone
Arturo
A
Del Valle
Luis
L
Amini
Shohreh
S
Khalili
Kamel
K
Turco
Maria Caterina
MC
D015526:AIDS Dementia Complex / Q000235:genetics / Q000821:virology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000502:physiology; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics* / Q000473:pathology / Q000821:virology; D016325:HIV Long Terminal Repeat / Q000502:physiology; D015497:HIV-1 / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008214:Lymphocytes / Q000473:pathology / Q000821:virology; D017628:Microglia / Q000473:pathology / Q000821:virology; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D004279:DNA, Viral; D016328:NF-kappa B