Poster abstracts
Poster number 1 submitted by Jacob Al-Saleem
Identification and Characterization of Novel Tax-1 Interacting Protein, SNX27, and its Role in HTLV-1 Pathobiology
Jacob Al-Saleem (Center for Retrovirus Research, The Ohio State University, Columbus, OH, USA; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA), Mamuka Kvaratskhelia (Center for Retrovirus Research, The Ohio State University, Columbus, OH, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA), Lee Ratner (Division of Oncology, Washington University, St Louis, MO, USA), O John Semmes (The Leroy T Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, Virginia, USA), Patrick L. Green (Center for Retrovirus Research, The Ohio State University, Columbus, OH, USA; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA)
Abstract:
Background: HTLV-1 and HTLV-2 are highly related viruses, with differential pathogenic outcomes in humans. While HTLV-1 is associated with several diseases, such as adult T cell leukemia, HTLV-2 is not associated with disease. The trans-activator of HTLV-1, Tax-1, has higher transforming potential then its HTLV-2 homolog, Tax-2. It is believed that this difference in transforming capacity plays a pivotal role in HTLV-1 pathogenesis. We propose that Tax-1 interacts with cellular gene products via domains lacking in Tax-2, and that these interactions contribute to pathogenesis.
Methods: We performed proteomic screens of Tax-1 binding partners utilizing Tax-1 mutants to identify these interactions. Novel interactions were confirmed and mapped by co-immunoprecipitation studies and further characterized by biochemical and biologic assays.
Results: We identified a novel interacting partner of Tax-1, Sorting Nexin 27 (SNX27). SNX27 regulates the localization and expression of transmembrane proteins via interactions with its PDZ domain. SNX27 has been demonstrated to regulate glucose transporter 1 (GLUT1); SNX27 knock down in HeLa cells results in a dramatic redistribution of GLUT1 from the cell surface to the lysosome. GLUT1 serves as one of three receptor molecules for HTLV-1. We propose that Tax-1 alters GLUT1 localization post-infection via its interaction with SNX27. We demonstrate that Tax‑1 and SNX27 interact via their PDZ domain binding motif (PBM) and PDZ domains, respectively. We further show that SNX27 expression levels are inversely related to virus release and that GLUT1 surface localization is reduced by Tax-1 overexpression in a dose-dependent manner. Other biologic effects of the Tax-1/SNX27 interaction and implications will be discussed.
Conclusion: This work demonstrates a novel mechanism by which HTLV-1 regulates a surface receptor molecule post-infection and this interaction could serve as a target to inhibit viral spread.
Keywords: HTLV, Tax-1, SNX27