Molecular determinants of PDLIM2 in suppressing HTLV-I Tax-mediated tumorigenesis.
Human T-cell leukemia virus type I (HTLV-I) encodes a Tax oncoprotein that has crucial roles in both virus replication and cell transformation. Our recent studies suggest that the counterbalance between HTLV-I/Tax and PDZ-LIM domain-containing protein PDLIM2 may determine the outcome of HTLV-I infection. Although HTLV-I represses PDLIM2 epigenetically and specifically in transformed cells, PDLIM2 shuttles Tax into the nuclear matrix for ubiquitination-mediated proteasomal degradation, thereby suppressing the transforming ability of HTLV-I. Here, we have further shown that PDLIM2 binds to Tax directly, which was mediated by a putative α-helix motif of PDLIM2 at amino acids 236-254. Consistently, selective disruption of this short-helix crippled PDLIM2 in shutting Tax to the nuclear matrix for ubiquitination-mediated degradation, therefore, PDLIM2 lost the ability in tumor suppression. Although the C-terminal LIM domain of PDLIM2 was not required for Tax binding, it was important for PDLIM2 to interact with the nuclear matrix. Accordingly, the LIM domain was essential for PDLIM2-mediated Tax repression. On the contrary, the N-terminal PDZ domain of PDLIM2 was dispensable for all these events, although the PDZ domain was involved in PDLIM2 binding to cytoskeleton. These studies dissect functional sequences within PDLIM2 and their distinct roles in Tax regulation.
Fu
J
J
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Yan
P
P
Li
S
S
Qu
Z
Z
Xiao
G
G
D020816:Amino Acid Motifs; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D016356:Gene Products, tax / Q000378:metabolism*; D015490:HTLV-I Infections / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins; D008840:Microfilament Proteins / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D013601:T-Lymphocytes / Q000378:metabolism
D016356:Gene Products, tax; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; C502929:PDLIM2 protein, human; C514970:tax protein, Human T-lymphotrophic virus 1