The Ubiquitin Ligase Siah1 Controls ELL2 Stability and Formation of Super Elongation Complexes to Modulate Gene Transcription

Liu, Min; Hsu, Joanne H.; Chan, Caleb; Li, Zichong; Zhou, Qiang

doi:10.1016/j.molcel.2012.03.007

Cited by 58 publications

(113 citation statements)

References 41 publications

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“…6B). This decrease could be due to the loss of AFF4's protection of ELL2 from the E3 ubiquitin ligase Siah1 (26). Apparently, the degree of protection varied between the two cell types.…”

Section: Resultsmentioning

confidence: 99%

A Minor Subset of Super Elongation Complexes Plays a Predominant Role in Reversing HIV-1 Latency

Zhou

2016

Molecular and Cellular Biology

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؉ T cells. Here, we used the CRISPRCas9 genome-editing tool to knock out the gene encoding the SEC subunit ELL2, AFF1, or AFF4 in Jurkat/2D10 cells, a well-characterized HIV-1 latency model. Depletion of these proteins drastically reduced spontaneous and drug-induced latency reversal by suppressing HIV-1 transcriptional elongation. Surprisingly, a low-abundance subset of SECs containing ELL2 and AFF1 was found to play a predominant role in cooperating with Tat to reverse latency. By increasing the cellular level/activity of these Tatfriendly SECs, we could potently activate latent HIV-1 without using any drugs. These results implicate the ELL2/AFF1-SECs as an important target in the future design of a combinatorial therapeutic approach to purge latent HIV-1. HIV-1 latency, which is characterized by transcriptional silence of the integrated proviruses, is the principal impediment to eradication of viral infection. Although antiretroviral therapy (ART) has been used successfully to drive HIV-1 into this silent state, thereby decreasing the plasma viremia to undetectable levels, the proviruses can quickly resume transcription and active replication once ART is interrupted (1). To obtain a real cure for HIV/AIDS, one strategy nicknamed "shock and kill" has been proposed to eliminate the latent viral reservoirs by first activating the proviruses in infected cells. This is followed by the next phase, where spread of the activated viruses can be suppressed by ART and the virus-producing cells are eliminated simultaneously (2).A number of cytokines and small-molecule drugs that include histone deacetylase inhibitors (HDACi), protein kinase C (PKC) agonists, BET bromodomain inhibitors, and others have been tested for their latency-reversing potentials (3, 4). However, virtually all of them have been found to display low efficacy and/or unacceptable side effects, which have limited their clinical use (3). Thus, better and more-specific means to activate the latent proviruses are urgently needed, which can be achieved only through in-depth characterization of the molecular mechanism and factors that control viral latency.Without stimulation, RNA polymerase II (Pol II), which transcribes the integrated proviral DNA, has a strong tendency to pause and then terminate near the transcription start site, resulting in the production of only short transcripts (5). This abortive transcription presents a major hurdle to efficient escape of HIV-1 from latency (2). To overcome this hurdle, a multicomponent complex containing the virally encoded Tat protein and its specific host cofactors must form on the nascent 5= end of the HIV-1 transcript, which folds into a stem-loop structure called the TAR (transactivation response) RNA. This Tat/TAR-containing complex converts the paused Pol II into a highly processive form capable of generating the full-length HIV-1 transcripts (5). In 2010, a set of human transcription factor complexes, called the super elongation complexes (SECs), was identified as the specific Tat cofactor (6, 7). A typica...

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“…6B). This decrease could be due to the loss of AFF4's protection of ELL2 from the E3 ubiquitin ligase Siah1 (26). Apparently, the degree of protection varied between the two cell types.…”

Section: Resultsmentioning

confidence: 99%

A Minor Subset of Super Elongation Complexes Plays a Predominant Role in Reversing HIV-1 Latency

Zhou

2016

Molecular and Cellular Biology

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“…However, this is just a hypothesis and it is necessary to globally and precisely define the number of SIAH1-/SIAH2-controlled proteins to test it. This task remains to be completed and so far only a few proteins have been found to be regulated by one of SIAH1 or SIAH2 but not by the other [5][6][7][8][9].…”

Section: Regulation Of Siah Expression By Hormones and Cytokinesmentioning

confidence: 99%

“…Although SIAH1 and SIAH2 often share substrate homology, specific targets of SIAH1 or SIAH2 have been described [5][6][7][8][9]. Genetic and biochemical evidence suggests that individual amino acid moieties within SIAH1 and SIAH2 determine their substrate functionality; i.e.…”

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confidence: 99%

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The inducible E3 ubiquitin ligases SIAH1 and SIAH2 perform critical roles in breast and prostate cancers

Knauer

Mahendrarajah

Roos

et al. 2015

Cytokine & Growth Factor Reviews

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“…Recently, ELL2 was shown to be a polyubiquitinated protein and the ubiquitination is carried out by the RING (a really interesting new gene) domain protein Siah1, which is identified as an E3 ubiquitin ligase for ELL2 (Liu et al, 2012). The interaction of ELL2 with the scaffolding protein AFF1/4 dramatically increases the stability of ELL2 and this stabilization is further enhanced by the presence of Tat (He et al, 2010), which in turn promotes SEC formation and SEC-dependent HIV-1 transcription.…”

Section: Tat Assembles the Super Elongation Complex (Sec) To Promote mentioning

confidence: 99%

Mechanism and factors that control HIV-1 transcription and latency activation

Liu

Shao

et al. 2014

J. Zhejiang Univ. Sci. B

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Abstract:After reverse transcription, the HIV-1 proviral DNA is integrated into the host genome and thus subjected to transcription by the host RNA polymerase II (Pol II). With the identification and characterization of human P-TEFb in the late 1990s as a specific host cofactor required for HIV-1 transcription, it is now believed that the elongation stage of Pol II transcription plays a particularly important role in regulating HIV-1 gene expression. HIV-1 uses a sophisticated scheme to recruit human P-TEFb and other cofactors to the viral long terminal repeat (LTR) to produce full-length HIV-1 transcripts. In this process, P-TEFb is regulated by the reversible association with various transcription factors/ cofactors to form several multi-subunit complexes (e.g., 7SK snRNP, super elongation complexes (SECs), and the Brd4-P-TEFb complex) that collectively constitute a P-TEFb network for controlling cellular and HIV-1 transcription. Recent progresses in HIV-1 transcription were reviewed in the paper, with the emphasis on the mechanism and factors that control HIV-1 transcription and latency activation.

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The Ubiquitin Ligase Siah1 Controls ELL2 Stability and Formation of Super Elongation Complexes to Modulate Gene Transcription

Cited by 58 publications

References 41 publications

A Minor Subset of Super Elongation Complexes Plays a Predominant Role in Reversing HIV-1 Latency

A Minor Subset of Super Elongation Complexes Plays a Predominant Role in Reversing HIV-1 Latency

The inducible E3 ubiquitin ligases SIAH1 and SIAH2 perform critical roles in breast and prostate cancers

Mechanism and factors that control HIV-1 transcription and latency activation

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