Calcium-dependent enhancement of transcription of p300 by human T-lymphotropic type 1 p12I

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) p12I localizes to the endoplasmic reticulum and Golgi causing sustained release of calcium, T cell activation, and enhanced expression of several calcium-regulated genes. In recent microarray studies, p300 mRNA was increased in T cells expressing p12I. The co-activator p300 is a key regulator of cellular and viral transcription; however, factors that influence its transcriptional regulation are less well studied. We hypothesized that the transcription of p300 is calcium dependent and that sustained low magnitude increases in intracellular calcium may enhance the transcription of p300. Herein, we report enhanced expression of p300 in T cells by p12I in a calcium-dependent, but calcineurin-independent manner. Sustained low magnitude calcium release induced by ionomycin in T cells was sufficient to increased mRNA and protein levels of p300 resulting in enhanced transcription from a p300-dependent promoter. Promoter analysis of the p300 gene was used to predict calcium-responsive transcription factor binding sites. Using mutant forms of p12I, we demonstrate that ER localization of the viral protein is required to increase p300. In addition, p12I reversed the repression of HTLV-1 LTR-driven transcription by HTLV-1 p30II, a p300-binding protein. HTLV-1 p12I-mediated enhancement of p300 expression represents a novel mechanism of regulation of cellular gene expression by viral proteins. By targeting a ubiquitous second messenger such as calcium, HTLV-1 p12I may regulate the expression of the cellular transcriptional co-activator p300 to modulate viral gene expression and promote lymphocyte survival.

Involvement of p300 in constitutive and HIV‐1 Tat‐activated expression of glial fibrillary acidic protein in astrocytes

“…Compared with its well‐characterized biological functions, only a very few studies have reported on its transcriptional regulation. Transcription factor early growth response 1 (Egr‐1) has been shown to regulate p300 transcription through the Egr‐1 DNA‐binding cis ‐acting elements within the p300 promoter, intracellular signaling, or viral infection or expression of viral protein (Cai et al, 2006; Nair et al, 2006; Saegusa et al, 2008; Yu et al, 2004). Meanwhile, Tat is known to alter various intracellular signaling pathways (Liu et al, 2002; Peruzzi, 2006).…”

Human T-Cell Leukemia Virus Type 1 (HTLV-1) p12IDown-Modulates ICAM-1 and -2 and Reduces Adherence of Natural Killer Cells, Thereby Protecting HTLV-1-Infected Primary CD4+T Cells from Autologous Natural Killer Cell-Mediated Cytotoxicity despite the Reduction of Major Histocompatibility Complex Class I Molecules on Infected Cells

“…This may involve the translocation of ICAMs from the endoplasmic reticulum to the proteasome as opposed to its normal pathway of migrating from the endoplasmic reticulum to the Golgi and finally to the surface, similar to p12 I -mediated down-modula- I modulates the expression of various calcium-regulated genes involved in cell adhesion, presumably by modulating the expression of transcriptional regulators such as p300 (52,53). The ICAM-1 promoter contains potential binding sites for a variety of transcriptional regulatory factors, including the CRE motif that can bind to p300/CBP complex (19,70).…”

Role of HTLV-1 orf-I encoded proteins in viral transmission and persistence

“…Additional studies have revealed that p8, which localizes at the cell surface, is also capable of downregulating NFAT activity, though in a LAT-dependent manner [68]. Besides NFAT, p12 expression influences other calcium-regulated proteins, like the transcriptional coactivator p300 [69], which can in turn modulate the transcription of viral genes from the HTLV-1 LTR [70]. Moreover, p12 can promote intercellular viral spread by inducing lymphocyte function-associated antigen 1 (LFA-1) clustering on T-cells through a calcium-dependent mechanism (Fig.…”