Abstract 1067: HTLV-1 Tax deregulates autophagy in promoting T-cell survival and proliferation.
Authors: Ren Tong , Dong Wen , Takahashi Yoshinori , Loughran Thomas P. , Sun Shao-Cong , Wang Hong-gang , Cheng Hua 
Published: August 2014

The retroviral oncoprotein Tax from Human T cell leukemia virus type 1 (HTLV-1) is an etiological factor of adult T cell leukemia and lymphoma. HTLV-1 viral genome-encoded oncoprotein, Tax, plays a pivotal role for promoting viral replication and initiating malignant transformation of CD4+ T lymphocytes. Tax deregulates various oncogenic signaling pathways including IκB kinase (IKK)/NF-κB, STAT3 and PI3K/Akt for aberrant proliferation of infected T cells. Tax activates IKK complex in the cytoplasm, resulting in persistent activation of NF-κB, a transcriptional factor that plays key roles in the pathogenesis of chronic inflammation and cancer. The IKK complex can be activated by divergent upstream kinases that connect it to signals from cell surface receptors such as T cell receptor (TCR). Upon T cell activation, IKKs are recruited to the plasma membrane lipid raft microdomains where they become catalytically active. Lipid raft microdomains are detergent-resistant membrane structure enriched with cholesterol and sphingolipids and serve as crucial signal transduction platforms. Distinct from TCR activation, Tax bypasses upstream kinases to directly target IKKγ, thereby recruiting the IKK complex to the lipid raft microdomains for activation. The IKK complex has been implicated to play an important role in starvation- or rapamycin-induced autophagy, though the underlying mechanism is not yet determined. Autophagy is a catabolic process that involves degradation of unnecessary or dysfunctional cellular proteins and organelles through lysosomal machinery. In response to metabolic stress, autophagy process generates energy for the need of metabolically stressed cells, and hence, the primary function of autophagy is pro-survival. The autophagic process is regulated by a variety of oncogenic signaling pathways. Given the evidence that HTLV-1 mediates oncogenic activation, it is conceivable that HTLV-1 may deregulate autophagy for its own benefits in viral oncogenesis. We here report that Tax is the causative factor for induction of autophagy in HTLV-1-transformed T cells and Tax-immortalized CD4 memory T cells. Tax deregulates autophagy by activating the IκB kinase complex, which subsequently recruits the autophagy molecule complex containing Bif-1, Beclin 1 and PI3KC3 to the lipid raft microdomains. By connecting the IkB kinase complex to the autophagy molecule complex, Tax facilitates assembly of LC3+ autophagosomes. Expression of the lipid raft targeted Bif-1 or Beclin1 is sufficient to form LC3+ autophagosomes, indicating that Tax recruitment of the autophagic molecules to lipid rafts is the main strategy to deregulate autophagy. Further, depletion of Beclin 1, the key mediator of autophagy pathway, results in growth arrest of the leukemic cells. Together, our data suggest an essential role of Tax-mediated autophagy in promoting survival and malignant transformation of virally infected T cells.

Citation Format: Tong Ren, Wen Dong, Yoshinori Takahashi, Thomas P. Loughran, Shao-Cong Sun, Hong-gang Wang, Hua Cheng. HTLV-1 Tax deregulates autophagy in promoting T-cell survival and proliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1067. doi:10.1158/1538-7445.AM2013-1067