T cell leukemia virus type 1 (HTLV-1) is a causative factor for adult T cell leukemia and lymphoma (ATLL). HTLV-1 genome encodes a viral transforming protein, Tax1, which plays an essential role in initiating oncogenesis. One of the critical features that Tax1 contributes to oncogenesis is induction of persistent activation of NF-(B. Yet, how this activity correlates with T cell transformation remains unsolved. Our work demonstrates that Tax1 is a critical lipid raft modulator that can hijack I(B kinases (IKKs) to the lipid raft microdomains in HTLV-1-transformed T cells. It is well recognized that enrichment of IKKs in the lipid raft microdomains leads to activation of NF-(B in antigen-stimulated T cells. Tax1 is able to recruit IKKs persistently in lipid rafts, correlating with persistent NF-(B activity. We also find that Tax1 sequesters beclin 1 (BECN1) and Bif-1, the essential autophagy mediators, in lipid rafts in IKK(- dependent manner. Conversely, BECN1 represses Tax1 activation of NF-(B by inhibiting IKK(. Since loss of BECN1 or Bif-1 has been linked to spontaneous tumorigenesis including lymphoma, our findings strongly suggest that Tax1 links IKK( activation to oncogenesis partly through its anti-autophagy activity. The rationale for this proposal is based on the assumption that the axis of Tax1-IKK(-BECN1/Bif-1 leads to "loss of function" of the autophagy mediators. The proposed research is both innovative and significant, representing a new concept in filling a giant gap for our understanding about how Tax initiates oncogenic transformation of T cells. Our central hypothesis is that "HTLV-1 Tax suppresses autophagy by hijacking IKK( to lipid rafts leading to sequestration of the autophagy mediators in the microdomains, thereby contributing significantly to oncogenesis". We plan to investigate this hypothesis with following specific aims.
Aim#1 : Define the domain critical for lipid raft targeting of Tax1. We will determine the motifs and modifications such as ubiquitination crucial for lipid raft targeting of Tax1, identify a cellular factor in assisting lipid raft association of Tax1, and assess the importance of the lipid raft association of Tax1 in immortalizing primary human CD4+ T cells and in transforming NIH3T3 cells.
Aim#2 : Investigate the underlying mechanism of Tax1 to deregulate autophagy. We will investigate the mechanism of Tax1 in sequestrating Bif-1 and BECN1 in lipid rafts, evaluate the inhibitory effect of BECN1 on Tax1 activation of IKK(, and examine anti-autophagy and tumorigenic activity of Tax1 using MEF (Bif1+/+) and (Bif1-/-) cells.
Aim#3 : Determine oncogenic potential and anti-autophagy function of lipid raft-targeted IKK(. We will evaluate physical and functional interaction of IKK( with Bif-1 and BECN1 and assess anti-autophagy and in vitro transforming activities of the lipid raft-targeted IKK(. This study will help to decipher the pathological role of the axis of Tax- IKK(-BECN1/Bif-1 in HTLV-1 oncogenesis.

Public Health Relevance

Adult T cell leukemia/lymphoma (ATLL) is caused by infection with human T cell leukemia virus type 1 (HTLV-1), infecting over 20 million patients worldwide. HTLV-1 encodes a viral oncogenic protein Tax, which plays an essential role in initiating malignancy of human T cells partly through persistent activation of NF-(B. We plan to investigate the mechanism that Tax mediates persistent activation of NF-(B and anti-autophagy function during development of T cell leukemia.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI090113-03
Application #
8312465
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Park, Eun-Chung
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2012
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Zhang, Huan; Chen, Li; Cai, Shao-Hui et al. (2016) Identification of TBK1 and IKKε, the non-canonical IκB kinases, as crucial pro-survival factors in HTLV-1-transformed T lymphocytes. Leuk Res 46:37-44
Niu, Ge; Zhang, Huan; Liu, Dan et al. (2015) Tid1, the Mammalian Homologue of Drosophila Tumor Suppressor Tid56, Mediates Macroautophagy by Interacting with Beclin1-containing Autophagy Protein Complex. J Biol Chem 290:18102-10
Ren, T; Takahashi, Y; Liu, X et al. (2015) HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains. Oncogene 34:334-45
Chen, Li; Liu, Dan; Zhang, Yang et al. (2015) The autophagy molecule Beclin 1 maintains persistent activity of NF-κB and Stat3 in HTLV-1-transformed T lymphocytes. Biochem Biophys Res Commun 465:739-45
Xiang, Di; Yuan, Yunsheng; Chen, Li et al. (2015) Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes. Biochem Biophys Res Commun 464:221-8
Chen, Li; Liu, Dan; Zhang, Yang et al. (2015) Foxp3-dependent transformation of human primary CD4+ T lymphocytes by the retroviral protein tax. Biochem Biophys Res Commun 466:523-9
Ren, Tong; Yang, Jun; Broeg, Katie et al. (2013) Developing an in vitro model of T cell type of large granular lymphocyte leukemia. Leuk Res 37:1737-43
Cheng, Hua; Ren, Tong; Sun, Shao-cong (2012) New insight into the oncogenic mechanism of the retroviral oncoprotein Tax. Protein Cell 3:581-9
Ren, Tong; Dong, Wen; Takahashi, Yoshinori et al. (2012) HTLV-2 Tax immortalizes human CD4+ memory T lymphocytes by oncogenic activation and dysregulation of autophagy. J Biol Chem 287:34683-93