Tip110: Physical properties, primary structure, and biological functions

Whitmill, Amanda; Timani, Khalid Amine; Liu, Ying; He, Johnny J.

doi:10.1016/j.lfs.2016.02.062

Cited by 19 publications

(42 citation statements)

References 77 publications

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“…Expression was mostly nuclear in the ICM and both nuclear and cytoplasmic in the TE cells. In the nucleus, Tip110 plays roles in a variety of processes but most notably regulation of pre‐mRNA splicing and gene transcription .…”

Section: Discussionmentioning

confidence: 99%

“…S1A). These targeted exons code for the nuclear localization signals, the RNA recognition motifs, and the LSm interaction motif of Tip110 (15,34), which are essential for a functional Tip110 protein. Tip110 tri-flox transgenic founder mice were generated and crossbred with EIIa-Cre transgenic mice, which have cre expression under the adenovirus EIIa promoter to express the Cre recombinase as early as the zygote stage [30].…”

Section: Generation Of Tip110-deficient Micementioning

confidence: 99%

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Tip110 Deletion Impaired Embryonic and Stem Cell Development Involving Downregulation of Stem Cell Factors Nanog, Oct4, and Sox2

et al. 2017

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HIV-1 Tat-interacting protein of 110 kDa, Tip110, plays important roles in multiple biological processes. In this study, we aimed to characterize the function of Tip110 in embryonic development. Transgenic mice lacking expression of a functional Tip110 gene (Tip110 -/-) died postimplantation, and Tip110 -/-embryos exhibited developmental arrest between 8.5 and 9.5 days post coitum. However, in vitro cultures of Tip110 -/-embryos showed that Tip110 loss did not impair embryo growth from the zygote to the blastocyst. Extended in vitro cultures of Tip110 -/-blastocysts showed that Tip110 loss impaired both blastocyst outgrowth and self-renewal and survival of blastocyst-derived embryonic stem cells. Microarray analysis of Tip110 -/-embryonic stem cells revealed that Tip110 loss altered differentiation, pluripotency, and cycling of embryonic stem cells and was associated with downregulation of several major stem cell factors including Nanog, Oct4, and Sox2 through a complex network of signaling pathways. Taken together, these findings document for the first time the lethal effects of complete loss of Tip110 on mammalian embryonic development and suggest that Tip110 is an important regulator of not only embryonic development but also stem cell factors. STEM CELLS 2017;35:1674-1686 SIGNIFICANCE STATEMENTHIV-1 Tat-interacting protein of 110 kDa (Tip110) is a nuclear protein with several important biological functions including pre-mRNA alternate splicing and gene transcription. In this study, we determined its role in mammalian embryonic development and the underlying molecular mechanisms. Using the conditional knockout strategy, we showed that loss of the Tip110 gene impaired embryonic development and stem cell pluripotency, self-renewal and survival. We further demonstrated that Tip110 deletion altered expression of stem cell factors such as Nanog, Oct4, and Sox2 in mouse embryonic stem cells through a complex gene network. These findings represent significant advances in our understanding of the biological function of Tip110 and suggest that Tip110 is important for embryonic development and regulation of stem cell factor expression.

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Section: Discussionmentioning

confidence: 99%

Section: Generation Of Tip110-deficient Micementioning

confidence: 99%

Tip110 Deletion Impaired Embryonic and Stem Cell Development Involving Downregulation of Stem Cell Factors Nanog, Oct4, and Sox2

et al. 2017

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“…The entire HAT repeat domain can be divided into two subdomains as follows: HAT-N-containing repeats 1-5 and HAT-C-containing repeats 6 -12. A linker helix, L␣, connects HAT-N and HAT-C. An additional C-terminal helix, E␣, links the HAT domain to a bipartite NLS peptide (10,23,24). We assigned the helices in the convex surface of the subdomains as ␣As, and those in the concave surface as ␣Bs, as this gives the best alignment of the sequence motifs (Fig.…”

Section: Sart3 Is a Dimer Containing 12 Hat Repeats-mentioning

confidence: 99%

“…It is also a potential antigen for cancer immunotherapy (7)(8)(9). The biological functions of SART3 have been summarized in a recent comprehensive review (10). SART3 is a large protein of 110 kDa and contains multiple half-a-tetratricopeptide (HAT) repeats followed by a bipartite nuclear localization sequence (NLS), two RNA recognition motifs, and a C-terminal conserved LSm-interacting motif (Fig.…”

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confidence: 99%

Structural Basis of the Recruitment of Ubiquitin-specific Protease USP15 by Spliceosome Recycling Factor SART3

Zhang

Harding

Hou

et al. 2016

Journal of Biological Chemistry

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Ubiquitin-specific proteases (USPs) USP15 and USP4 belong to a subset of USPs featuring an N-terminal tandem domain in USP (DUSP) and ubiquitin-like (UBL) domain. Squamous cell carcinoma antigen recognized by T-cell 3 (SART3), a spliceosome recycling factor, binds to the DUSP-UBL domain of USP15 and USP4, recruiting them to the nucleus from the cytosol to control deubiquitination of histone H2B and spliceosomal proteins, respectively. To provide structural insight, we solved crystal structures of SART3 in the apo-form and in complex with the DUSP-UBL domain of USP15 at 2.0 and 3.0 Å, respectively. Structural analysis reveals SART3 contains 12 half-a-tetratricopeptide (HAT) repeats, organized into two subdomains, HAT-N and HAT-C. SART3 dimerizes through the concave surface of HAT-C, whereas the HAT-C convex surface binds USP15 in a novel bipartite mode. Isothermal titration calorimetry measurements and mutagenesis analysis confirmed key residues of USP15 involved in the interaction and indicated USP15 binds 20-fold stronger than USP4.Ubiquitination plays an important role in almost every biological process, including protein homeostasis, DNA damage response, gene transcription, protein trafficking, and RNA splicing. Deubiquitinases (DUBs) 2 remove covalently conjugated ubiquitin tags from substrates and regulate ubiquitin signaling. Ubiquitin-specific proteases (USPs) comprise the largest family of DUBs. In addition to the catalytic domain, most USPs contain auxiliary domains that are involved in substrate recognition, activity regulation, or recruitment of binding partners (1, 2). USP4, USP11, and USP15 are a small set of closely related USPs, sharing a similar domain architecture as follows: a DUSP (domain in USP), followed by a ubiquitin-like (UBL) and a large catalytic domain, bifurcated by a second UBL domain and disordered region (Fig. 1A). Evolutionary analysis suggests the three USPs arose from gene duplication events (3). USP4 and USP15 are more closely related in both sequence and function compared with USP11. Both USP4 and USP15 are implicated in mRNA processing through their interaction with spliceosome components (1). USP4 is recruited by U4/U6 small nuclear RNA recycling factor SART3 (squamous cell carcinoma antigen recognized by T cells 3) to remove the Lys-63-polyubiquitin chain from pre-mRNA processing factor 3 (Prp3), and it controls the assembly of the spliceosome at distinct stages of the splicing process (4). USP15, but not USP4, is recruited by SART3 to regulate deubiquitination of free ubiquitinated histone H2B that has been evicted from the nucleosome during transcription (5).SART3 is the mammalian homolog of yeast Prp24 protein and is essential for the formation of U4/U6 small nuclear ribonucleoprotein complex (6). SART3 plays multiple roles in mRNA splicing, viral and host gene transcription, as well as stem cell survival, proliferation, and differentiation. It is also a potential antigen for cancer immunotherapy (7-9). The biological functions of SART3 have been summarized in a recent c...

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“…Several studies have reported a direct and specific contact of SART3 with both unphosphorylated RNAPII and Tat, promoting P-TEFb recruitment directly to the TAR/Tat/P-TEFb complex, leading to Ser2 phosphorylation of the RNAPII CTD and transcription elongation [103, 104]. The role of SART3 on HIV transcription has been recently reviewed by Whitmill et al [105]. …”

Section: Early Events In Tat-mediated Hiv-1 Transcriptionmentioning

confidence: 99%

Role of Host Factors on the Regulation of Tat-Mediated HIV-1 Transcription

Mousseau

Valente

2017

CPD

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Background The viral transactivator Tat protein is a key modulator of HIV-1 replication, as it regulates transcriptional elongation from the integrated proviral genome. Tat recruits the human transcription elongation factor b, and other host proteins, such as the super elongation complex, to activate the cellular RNA polymerase II, normally stalled shortly after transcription initiation at the HIV promoter. By means of a complex set of interactions with host cellular factors, Tat determines the fate of viral activity within the infected cell. The virus will either actively replicate to promote dissemination in blood and tissues, or become dormant mostly in memory CD4+ T cells, as part of a small but long-living latent reservoir, the main obstacle for HIV eradication. Objective In this review, we summarize recent advances in the understanding of the multi-step mechanism that regulates Tat-mediated HIV-1 transcription and RNA polymerase II release, to promote viral transcription elongation. Early events of the human transcription elongation factor b release from the inhibitory 7SK small nuclear ribonucleoprotein complex and its recruitment to the HIV promoter will be discussed. Specific roles of the super elongation complex subunits during transcription elongation, and insight on recently identified cellular factors and mechanisms regulating HIV latency will be detailed. Conclusion Understanding the complexity of HIV transcriptional regulation by host factors may open the door for development of novel strategies to eradicate the resilient latent reservoir.

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Tip110: Physical properties, primary structure, and biological functions

Cited by 19 publications

References 77 publications

Tip110 Deletion Impaired Embryonic and Stem Cell Development Involving Downregulation of Stem Cell Factors Nanog, Oct4, and Sox2

Tip110 Deletion Impaired Embryonic and Stem Cell Development Involving Downregulation of Stem Cell Factors Nanog, Oct4, and Sox2

Structural Basis of the Recruitment of Ubiquitin-specific Protease USP15 by Spliceosome Recycling Factor SART3

Role of Host Factors on the Regulation of Tat-Mediated HIV-1 Transcription

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