Regulation of Tat Acetylation and Transactivation Activity by the Microtubule-associated Deacetylase HDAC6

Abstract

Reversible acetylation of Tat is critical for its transactivation activity toward HIV-1 transcription. However, the enzymes involved in the acetylation/deacetylation cycles have not been fully characterized. In this study, by yeast two-hybrid assay, we have discovered the histone deacetylase HDAC6 to be a binding partner of Tat. Our data show that HDAC6 interacts with Tat in the cytoplasm in a microtubule-dependent manner. In addition, HDAC6 deacetylates Tat at Lys-28 and thereby suppresses Tatmediated transactivation of the HIV-1 promoter. Inactivation of HDAC6 promotes the interaction of Tat with cyclin T1 and leads to an increase in Tat transactivation activity. These findings establish HDAC6 as a Tat deacetylase and support a model in which Lys-28 deacetylation decreases Tat transactivation activity through affecting the ability of Tat to form a ribonucleoprotein complex with cyclin T1 and the transactivation-responsive RNA.

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 + T Lymphocytes

“…One potential candidate is the histone deacetylase HDAC6, whose deacetylase activity was shown to be regulated upon interaction with p62 (49). Furthermore, HDAC6 was also reported to deacetylate Tat, leading to a decrease in Tat transactivation activity (50).…”

Cellular defence or viral assist: the dilemma of HDAC6

“…Besides, tubulin acetylation is supposed to guide and accelerate the nuclear trafficking of post-entry viruses, and inhibition of HDAC6 by its specific inhibitors could apparently improve the replication efficiency of oncolytic viruses [84,85]. In addition, HDAC6 is capable of regulating the transactivation activity of Tat, a transactivator of transcription protein essential for HIV-1 transcription and replication [86]. HDAC6 can bind and deacetylate Tat at Lys 28 in an MTdependent manner.…”

“…For instance, the half-life of HIVderived peptides is reduced following HDAC6 depletion or in the presence of the chemical inhibitor TSA, indicating that HDAC6 protects peptides from cytosolic degradation. On the other hand, HDAC6 increases the antiviral function of CD8 + T cell in HTLV-1 infection with unclear mechanism [86]. One possible explanation for HDAC6-enhanced T cell-mediated cytotoxicity is that CTLs are highly motile cells and require a dynamic cytoskeleton to actively approach potential target cells, whereas inhibition of HDAC6 is known to reduce cell migration.…”

“…For instance, HIV latency arises when the regulatory feedback mechanism driven by the regulatory protein Tat is below threshold levels [151]. HDAC6 deacetylates Lys 28 of Tat in the nucleus and inhibits Tat transcriptional activity by triggering its export to the cytoplasm, thus maintaining HIV latency [86]. In contrast, HDAC6 regulates KSHV reactivation switch through a less clear mechanism [149].…”

Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells

“…HDAC6 has been shown to participate in a wide range of cellular processes primarily through its deacetylation of α-tubulin, the actin-binding protein cortactin, and the molecular chaperone heat shock protein 90 (Hubbert et al, 2002;Matsuyama et al, 2002;Zhang et al, 2003;Kovacs et al, 2005;Zhang et al, 2007). In addition, HDAC6 can form various complexes with partner proteins to regulate physiological or pathological processes (Parmigiani et al, 2008;Huo et al, 2011;Li et al, 2011). Over the past decade, there has been tremendous effort to develop effective and specific HDAC6 inhibitors for the treatment of human diseases including cancer, although their mechanisms of action remain largely elusive (Aldana-Masangkay and Sakamoto, 2011;Dallavalle et al, 2012).…”