HTLV-1 Tax upregulates early growth response protein 1 through nuclear factor-κB signaling

// Qingsong Huang 1, 2, 3, * , Zhiguo Niu 2, 3, * , Jingxian Han 4 , Xihong Liu 2 , Zhuangwei Lv 5 , Huanhuan Li 2 , Lixiang Yuan 2 , Xiangping Li 6 , Shuming Sun 1 , Hui Wang 2, 3 and Xinxiang Huang 1 1 School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China 2 Research Center for Immunology, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China 3 Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China 4 The 7th Hospital of Zhengzhou City, Zhengzhou, Henan, China 5 The Third Affiliated Hospital Of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, Henan, China 6 Luoyang Orthopedic-Traumatological Hospital, Zhengzhou, Henan, China * These authors contributed equally to this work Correspondence to: Xinxiang Huang, email: huxinx@ujs.edu.cn Hui Wang, email: immuneweb@126.com Keywords: HTLV-1, Tax, EGR1, NF-κB, adult T cell leukemia Received: May 11, 2016      Accepted: February 20, 2017      Published: May 08, 2017 ABSTRACT Human T cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that causes adult T cell leukemia (ATL) in susceptible individuals. The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-κB (NF-κB) pathway. Early growth response protein 1 (EGR1) is overexpressed in HTLV-1-infected T cell lines and ATL cells. Here, we showed that both Tax expression and HTLV-1 infection promoted EGR1 overexpression. Loss of the NF-κB binding site in the EGR1 promotor or inhibition of NF-κB activation reduced Tax-induced EGR1 upregulation. Tax mutants unable to activate NF-κB induced only slight EGR1 upregulation as compared with wild-type Tax, confirming NF-κB pathway involvement in EGR1 regulation. Tax also directly interacted with the EGR1 protein and increased endogenous EGR1 stability. Elevated EGR1 in turn promoted p65 nuclear translocation and increased NF-κB activation. These results demonstrate a positive feedback loop between EGR1 expression and NF-κB activation in HTLV-1-infected and Tax-expressing cells. Both NF-κB activation and Tax-induced EGR1 stability upregulated EGR1, which in turn enhanced constitutive NF-κB activation and facilitated ATL progression in HTLV-1-infected cells. These findings suggest EGR1 may be an effective anti-ATL therapeutic target.