Salt-inducible kinases function as a host restriction to human T-cell leukemia virus type 1 transcription

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 Tax is the major viral transactivator and transforming protein centrally involved in the proviral transcription, transformation and proliferation of infected T-cells as well as progression of diseases caused by HTLV-1 infection. Salt-inducible kinases (SIKs) are serine/threonine protein kinases belonging to the AMPK-related kinase (AMPK-RK) family. SIK subfamily consists of three isoforms named SIK1, SIK2 and SIK3 respectively. We have previously demonstrated the negative regulatory role of SIK1 in Tax-mediated activation of proviral transcription from long terminal repeats (LTR). In this study, we reported that both SIK2 and SIK3 exhibited a kinase-dependent suppressive effect on Tax-activated LTR transcription. We also found that SIK1, SIK2 and SIK3 act additively to suppress Tax activation of LTR. We further demonstrated that the SIK2- and SIK3-mediated suppression on LTR transcription was achieved through phosphorylation of TORC1, an essential transcriptional coactivator of CREB required for Tax-mediated transcriptional activation of LTR. Our findings revealed a new function of SIK2 and SIK3 in host restriction to HTLV-1 transcription. Pharmaceutical activation of SIKs or upstream kinase such as LKB1 may provide a new strategy for anti-HTLV-1 therapy.