Abstract
The HIV-1 matrix protein p17 is a structural protein that can act in the extracellular environment to deregulate several functions of immune cells, through the interaction of its NH2-terminal region with a cellular surface receptor (p17R). The intracellular events triggered by p17/p17R interaction have been not completely characterized yet. In this study we analyze the signal transduction pathways induced by p17/p17R interaction and show that in Raji cells, a human B cell line stably expressing p17R on its surface, p17 induces a transient activation of the transcriptional factor AP-1. Moreover, it was found to upregulate pERK1/2 and downregulate pAkt, which are the major intracellular signalling components involved in AP-1 activation. These effects are mediated by the COOH-terminal region of p17, which displays the capability of keeping PTEN, a phosphatase that regulates the PI3K/Akt pathway, in an active state through the serin/threonin (Ser/Thr) kinase ROCK. Indeed, the COOH-terminal truncated form of p17 (p17Δ36) induced activation of the PI3K/Akt pathway by maintaining PTEN in an inactive phosphorylated form. Interestingly, we show that among different p17s, a variant derived from a Ugandan HIV-1 strain, named S75X, triggers an activation of PI3K/Akt signalling pathway, and leads to an increased B cell proliferation and malignant transformation. In summary, this study shows the role of the COOH-terminal region in modulating the p17 signalling pathways so highlighting the complexity of p17 binding to and signalling through its receptor(s). Moreover, it provides the first evidence on the presence of a p17 natural variant mimicking the p17Δ36-induced signalling in B cells and displaying the capacity of promoting B cell growth and tumorigenesis.
Highlights
The three-dimensional structure of HIV-1 matrix protein p17, a 132 amino acid structural protein, has been determined by nuclear magnetic resonance and X-ray crystallography
These effects are mediated by the COOH-terminal region of p17, which displays the capability of keeping PTEN, a phosphatase that regulates the PI3K/Akt pathway, in an active state through the serin/threonin (Ser/Thr) kinase RhoA-associated kinase (ROCK)
Western blot analysis, performed using the monoclonal antibody MBS-3 which recognizes the functional epitope AT20 in the p17 NH2-terminal region [18,26], revealed that both monomeric and trimeric p17 are recognized by this mAb (Figure 1B)
Summary
The three-dimensional structure of HIV-1 matrix protein p17, a 132 amino acid (aa) structural protein, has been determined by nuclear magnetic resonance and X-ray crystallography. Individual folded p17 molecules result composed of five major a-helixes and a highly basic platform consisting of three b strands [1,2]. This partially globular protein presents four helixes centrally organized to form a compact globular domain capped by the b-sheet. The fifth helix (H5) in the COOH-terminus of the protein, projects away from the packed bundle of helixes to expose COOH-terminal residues essential for early steps during the HIV1 infectious cycle. The most distinguishing feature when comparing X-ray and NMR solved conformation of p17 is the folding of H5 and results obtained from Verli et al [3] suggest that the biological form of this protein may have its COOH-terminal portion partially unfolded
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