Louise Routier

Study of the role of the cellular factor CTIP2 in the transcriptional regulation of human T lymphotropic virus type 1 (HTLV-1)

Abstract

The CTIP2 protein is a cellular co-factor with an activator or repressor role in transcription, depending on its association with different complexes but also on the cellular and genomic environment. Previously, our laboratory discovered a role for CTIP2 in the transcriptional regulation of Human T-cell Leukemia Virus type 1 (HTLV-1) by a repression of Tax-mediated transactivation of the HTLV-1 promoter. Our laboratory has also identified acetylatable lysines of CTIP2 whose mutation of lysine 686 to arginine results in a global loss of acetylation of the protein as well as a loss of the repressive role of CTIP2 in Tax-mediated transactivation of the HTLV-1 5'LTR. In our thesis, we further investigated the involvement of CTIP2 and its lysine 686 in Tax-mediated transactivation of the HTLV-1 5'LTR. Our results showed that CTIP2 is able to repress Tax-mediated transactivation of the HTLV-1 promoter and that mutation of its lysine 686 impacts its repressor role. Furthermore, both wild-type and mutated CTIP2 result in a decrease of Tax protein expression that is not affected by blocking the proteasomal pathway. However, our preliminary results suggest that Tax protein may be degraded by the autophagy pathway in the presence of CTIP2. We showed that CTIP2 do not interact with Tax to repress the transactivation of HTLV-1 promoter. Surprisingly, our results demonstrated colocalization between CTIP2K686R and Tax proteins in the cytoplasm at the perinuclear level. We also showed that the mutation of the lysine 686 of CTIP2 impacts the cellular localization of the CTIP2 protein. In conclusion, our results allow a better understanding of the relationship between wild type and mutated CTIP2 and Tax but also of the role of CTIP2 in HTLV-1 viral latency.