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Abstract
The Siah1 and Siah2 ubiquitin ligases are implicated in diverse biological processes ranging from cellular stress responses, signaling to transcriptional regulation. A key substrate of Siah1 is ELL2, which undergoes proteolysis upon polyubiquitination. ELL2 stimulates transcriptional elongation and is a subunit of the Super Elongation Complex (SEC) essential for HIV-1 transactivation. Previously, multiple transcriptional and post-translational mechanisms are reported to control Siah's expression and activity. Here we show that the activity of Siah1/2 can also be suppressed by host cell factor 1 (HCF1), and the hitherto poorly characterized HCF2, which themselves are not degraded but can bind and block the substrate-binding domain (SBD) of Siah1/2 to prevent their autoubiquitination and trans-ubiquitination of downstream targets including ELL2. This effect stabilizes ELL2 and enhances the ELL2-SEC formation for robust HIV-1 transactivation. Thus, our study not only identifies HCF1/2 as novel activators of HIV-1 transcription through inhibiting Siah1 to stabilize ELL2, but also reveals the SBD of Siah1/2 as a previously unrecognized new target for HCF1/2 to exert this inhibition.
Highlights
Promoter-proximal pausing of freshly initiated RNA polymerase II (Pol II) on integrated HIV proviral DNA is a major rate-limiting step to restrict viral transcription [1,2]
host cell factor 1 (HCF1) and HCF2 are required for HIV-1 transcription and their cellular levels are insufficient for robust Tattransactivation
Recent evidence indicates that this complex is essential for efficient transcriptional elongation of the herpes simplex virus (HSV) Immediate Early (IE) genes, which employ promoter-proximal pausing and release of RNA Pol II as a key regulatory mechanism for expression [13]
Summary
Promoter-proximal pausing of freshly initiated RNA polymerase II (Pol II) on integrated HIV proviral DNA is a major rate-limiting step to restrict viral transcription [1,2]. To overcome this restriction, the HIV-1-encoded Tat protein binds and recruits the human Super Elongation Complex (SEC) to paused Pol II through forming a multi-component complex on the TAR RNA element, a stem-loop structure located at the 5 end of all nascent HIV-1 transcripts [2–5]. Upon recruitment by Tat and TAR to the HIV-1 promoter as integral components of a SEC, P-TEFb and ELL2 can synergistically activate Pol II elongation along the HIV-1 template to produce the full-length viral transcripts [2–5]
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