P-C1 Autophagy molecules are required for persistent activation of NF-κB and Stat3 in HTLV-1-transformed T lymphocytes

Abstract

Chronic infection of human T cell leukemia virus type 1 (HTLV-1) causes adult T cell leukemia and lymphoma (ATL), a specific type of hematological malignancy with characteristic features of enlarged lymph nodes, skin lesion and elevated calcium. It is known that the viral genome of HTLV-1 encodes the Tax oncoprotein that promotes viral replication and initiates malignant transformation of human T lymphocytes. Tax deregulates various oncogenic signaling molecules including induction of a constitutive activity of NF-kB, a prerequisite for the development of ATL. We have previously shown that HTLV-1-transformed T cells exhibit an increased autophagic flux and that Tax deregulates autophagy by interacting with the autophagy protein complex. Here, we show that autophagy molecules not only execute the cytoprotective function but also play a pivotal role in mediating Tax-induced activation of NF-κB and Stat3 in HTLV-1-transformed T cells. We find that depletion of the key autophagy mediator such as Beclin1, Atg5 or PI3 kinase class III (PI3KC3) results in diminished activities of NF-κB and Stat3 as well as impaired survival and proliferation of the HTLV-1-transformed T cells that express Tax. We also find that BAY11-8075, a selective IKK inhibitor, inhibits the activities of both NF-κB and Stat3. Furthermore, the NFκB-activating mutant of Tax is unable to induce Stat3 activation, and the depletion of IKKκ, an essential regulatory subunit of the IKK complex, leads to the significant reduction of the activities of both NF-κB and Stat3. These findings suggest that the activity of Stat3 is dependent on NFκB in HTLV-1-transformed T cells. Collectively, our study has identified a key role of the autophagy molecules to maintain the sustainable co-activation of NF-κB and Stat3 during chronic infection of HTLV-1, thereby promoting aberrant proliferation and transformation of HTLV-1-infected T cells. Our findings provide new insights into the development of an autophagy-targeted therapy for controlling HTLV-1-mediated oncogenesis.