Submitted October 22, 2008
Accepted December 16, 2008
PDLIM2 suppresses HTLV-I Tax-mediated tumorigenesis by targeting Tax into the nuclear matrix for proteasomal degradation
Pengrong Yan, Jing Fu, Zhaoxia Qu, Shirong Li, Takashi Tanaka, Michael J Grusby, and Gutian Xiao*
University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, United States
* Corresponding author; email: xiaog2{at}upmc.edu.
The mechanisms by which the human T-cell leukemia virus type I (HTLV-I) Tax oncoprotein deregulates cellular signaling for oncogenesis have been extensively studied, but how Tax itself is regulated remains largely unknown. Here we report that Tax was negatively regulated by PDLIM2, which promoted Tax K48-linked polyubiquitination. In addition, PDLIM2 recruited Tax from its functional sites into the nuclear matrix where the polyubiquitinated Tax was degraded by the proteasome. Consistently, PDLIM2 suppressed Tax-mediated signaling activation, cell transformation and oncogenesis both in vitro and in animal. Notably, PDLIM2 expression was down-regulated in HTLV-I-transformed T cells, and PDLIM2 reconstitution reversed the tumorigenicity of the malignant cells. These studies indicate that the counterbalance between HTLV-I/Tax and PDLIM2 may determine the outcome of HTLV-I infection. These studies also suggest a potential therapeutic strategy for cancers and other diseases associated with HTLV-I infection and/or PDLIM2 deregulation.
