Complex role of microRNAs in HTLV-1 infections

Abstract

Human T-lymphotropic virus 1 (HTLV-1) was the first human retrovirus to be discovered and is the causative agent of adult T-cell leukemia/lymphoma (ATL) and the neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The importance of microRNA (miRNA) in the replicative cycle of several other viruses, as well as in the progression of associated pathologies, has been well established in the past decade. Moreover, involvement of miRNA alteration in the HTLV-1 life cycle, and in the progression of its related oncogenic and neurodegenerative diseases, has recently come to light. Several HTLV-1 derived proteins alter transcription factor functionalities, interact with chromatin remodelers, or manipulate components of the RNA interference (RNAi) machinery, thereby establishing various routes by which miRNA expression can be up- or down-regulated in the host cell. Furthermore, the mechanism of action through which dysregulation of host miRNAs affects HTLV-1 infected cells can vary substantially and include mRNA silencing via the RNA-induced silencing complex (RISC), transcriptional gene silencing, inhibition of RNAi components, and chromatin remodeling. These miRNA-induced changes can lead to increased cell survival, invasiveness, proliferation, and differentiation, as well as allow for viral latency. While many recent studies have successfully implicated miRNAs in the life cycle and pathogenesis of HTLV-1 infections, there are still significant outstanding questions to be addressed. Here we will review recent discoveries elucidating HTLV-1 mediated manipulation of host cell miRNA profiles and examine the impact on pathogenesis, as well as explore future lines of inquiry that could increase understanding in this field of study.

Keywords: ATL; HAM/TSP; HTLV-1; NF-κB; RNAi; Tax; chromatin; miRNA.

Figure 1

HTLV-1 dysregulation of host miRNA profiles. HTLV-1 infected cells selectively up- and down-regulate numerous host cell miRNAs. Specifically, several miRNAs targeting the HATs P/CAF and p300 are decreased in HTLV-1 and Tax transfected cells, while other miRNAs targeting pro-apoptotic (TP53INP1) and immunomodulating genes (MICB) are up-regulated. The dysregulated miRNAs and target proteins detailed here represent only a small fraction of the cellular pathways manipulated by the HTLV-1 virus.

Figure 2

Tax mediated proteasomal degradation of Drosha. Tax binds to Drosha and drives subsequent ubiquitination and proteasomal degradation of the protein. This reduction in cellular levels of Drosha in turn leads to global down-regulation of host miRNAs by minimizing the enzymatic machinery to convert Pri-miRNAs to Pre-miRNAs.

Figure 3

Protein-protein interactions of HTLV-1 Tax with members of the NF-κB family of transcription factors. Dysregulation of the canonical pathway occurs with the interaction of ubiquitinylated Tax to the cytoplasmic IKK complex, specifically binding to the IKKγ subunit. This interaction results in the phosphorylation of IκB, as well as the ubiquitination and subsequent degradation of IκB through the proteasome pathway. RelA is subsequently activated and translocates into the nucleus where SUMOylated Tax recruits RelA to Tax-nuclear bodies, driving Tax-mediated NF-κB transcription. Similarly, ubiquitinylated Tax interacts with the IKKα complex to induce the processing of p100 to p52 within the non-canonical pathway. This promotes the phosphorylation, ubiquitination, and subsequent proteasomal degradation of p100, as well as the recruitment of RelB to the nucleus for activation of Tax-mediated NF-κB transcription. Xcr, transcription.