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Host Proteins Ku and HMGA1 As Participants of HIV-1 Transcription.

Shadrina OA, Knyazhanskaya ES, Korolev SP, Gottikh MB - Acta Naturae (2016 Jan-Mar)

Bottom Line: The latency maintenance is also a problematic question.We also describe the differential influence of the HMGA1 protein on the induced and basal transcription of HIV-1.Finally, we offer possible mechanisms for Ku and HMGA1 proteins in the proviral transcription regulation.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Leninskie Gory, Moscow, 119991, Russia.

ABSTRACT
Human immunodeficiency virus type 1 is known to use the transcriptional machinery of the host cell for viral gene transcription, and the only viral protein that partakes in this process is Tat, the viral trans-activator of transcription. During acute infection, the binding of Tat to the hairpin at the beginning of the transcribed viral RNA recruits the PTEFb complex, which in turn hyperphosphorylates RNA-polymerase II and stimulates transcription elongation. Along with acute infection, HIV-1 can also lead to latent infection that is characterized by a low level of viral transcription. During the maintenance and reversal of latency, there are no detectable amounts of Tat protein in the cell and the mechanism of transcription activation in the absence of Tat protein remains unclear. The latency maintenance is also a problematic question. It seems evident that cellular proteins with a yet unknown nature or role regulate both transcriptional repression in the latent phase and its activation during transition into the lytic phase. The present review discusses the role of cellular proteins Ku and HMGA1 in the initiation of transcription elongation of the HIV-1 provirus. The review presents data regarding Ku-mediated HIV-1 transcription and its dependence on the promoter structure and the shape of viral DNA. We also describe the differential influence of the HMGA1 protein on the induced and basal transcription of HIV-1. Finally, we offer possible mechanisms for Ku and HMGA1 proteins in the proviral transcription regulation.

No MeSH data available.


Related in: MedlinePlus

Model of HMGA-1-mediated repression of HIV-1 transcription. A– competition between HMGA1 and Tat for TAR reduces the activityof the viral promoter. Tat releases 7SK from its complex with P-TEFb bound tothe promoter. 7SK binds to HMGA1 to release TAR for subsequent interaction withTat-P-TEFb. B – in the absence of Tat, HMGA1 impedesbinding of a certain cellular cofactor, which is required for TAR-mediatedHIV-1 transcription, to TAR RNA. 7SK binds to HMGA1, thus releasing TAR forsubsequent interaction with this cofactor [4].
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Figure 10: Model of HMGA-1-mediated repression of HIV-1 transcription. A– competition between HMGA1 and Tat for TAR reduces the activityof the viral promoter. Tat releases 7SK from its complex with P-TEFb bound tothe promoter. 7SK binds to HMGA1 to release TAR for subsequent interaction withTat-P-TEFb. B – in the absence of Tat, HMGA1 impedesbinding of a certain cellular cofactor, which is required for TAR-mediatedHIV-1 transcription, to TAR RNA. 7SK binds to HMGA1, thus releasing TAR forsubsequent interaction with this cofactor [4].

Mentions: Another mechanism via which HMGA1 influences HIV-1 transcription was uncoveredwhile studying the expression of a reporter gene under the control of viral5’-LTR from a plasmid [4]. In thiscase, HMGA1 had a repressive effect. A detailed study of the mechanism of HMGA1action has shown that it can bind to TAR RNA due to the similarity between itsstructure and 7SK L2 RNA(Fig. 9);HMGA1 may compete withviral protein Tat for binding to TAR RNA. This results in a negative effect ofHMGA1 on HIV-1 transcription both in the presence and absence of Tat. Theinfluence of overexpression and knockdown of the HMGA1 geneand 7SK L2 RNA on transcription from the HIV-1 promoter was studied in thepresence and absence of Tat. HMGA1 was found to reduce both the basal andTat-activated transcription from the HIV-1 promoter, which is partiallyrecovered upon 7SK L2 RNA overexpression. Based on this experiment, the modelof HMGA1- mediated repression has been proposed(Fig. 10)[4]. According to this model, HMGA1impedes binding of TAR RNA with Tat, or, in the absence of Tat, with a cellularcofactor of viral transcription that has not been described yet. 7SK L2 RNAcompetes with TAR for HMGA1, destroys their complex, and takes away the HMGA1protein from the HIV-1 promoter. This facilitates transcription activation.However, the existence and nature of the putative cellular cofactor involved inthis process still remains open.


Host Proteins Ku and HMGA1 As Participants of HIV-1 Transcription.

Shadrina OA, Knyazhanskaya ES, Korolev SP, Gottikh MB - Acta Naturae (2016 Jan-Mar)

Model of HMGA-1-mediated repression of HIV-1 transcription. A– competition between HMGA1 and Tat for TAR reduces the activityof the viral promoter. Tat releases 7SK from its complex with P-TEFb bound tothe promoter. 7SK binds to HMGA1 to release TAR for subsequent interaction withTat-P-TEFb. B – in the absence of Tat, HMGA1 impedesbinding of a certain cellular cofactor, which is required for TAR-mediatedHIV-1 transcription, to TAR RNA. 7SK binds to HMGA1, thus releasing TAR forsubsequent interaction with this cofactor [4].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837570&req=5

Figure 10: Model of HMGA-1-mediated repression of HIV-1 transcription. A– competition between HMGA1 and Tat for TAR reduces the activityof the viral promoter. Tat releases 7SK from its complex with P-TEFb bound tothe promoter. 7SK binds to HMGA1 to release TAR for subsequent interaction withTat-P-TEFb. B – in the absence of Tat, HMGA1 impedesbinding of a certain cellular cofactor, which is required for TAR-mediatedHIV-1 transcription, to TAR RNA. 7SK binds to HMGA1, thus releasing TAR forsubsequent interaction with this cofactor [4].
Mentions: Another mechanism via which HMGA1 influences HIV-1 transcription was uncoveredwhile studying the expression of a reporter gene under the control of viral5’-LTR from a plasmid [4]. In thiscase, HMGA1 had a repressive effect. A detailed study of the mechanism of HMGA1action has shown that it can bind to TAR RNA due to the similarity between itsstructure and 7SK L2 RNA(Fig. 9);HMGA1 may compete withviral protein Tat for binding to TAR RNA. This results in a negative effect ofHMGA1 on HIV-1 transcription both in the presence and absence of Tat. Theinfluence of overexpression and knockdown of the HMGA1 geneand 7SK L2 RNA on transcription from the HIV-1 promoter was studied in thepresence and absence of Tat. HMGA1 was found to reduce both the basal andTat-activated transcription from the HIV-1 promoter, which is partiallyrecovered upon 7SK L2 RNA overexpression. Based on this experiment, the modelof HMGA1- mediated repression has been proposed(Fig. 10)[4]. According to this model, HMGA1impedes binding of TAR RNA with Tat, or, in the absence of Tat, with a cellularcofactor of viral transcription that has not been described yet. 7SK L2 RNAcompetes with TAR for HMGA1, destroys their complex, and takes away the HMGA1protein from the HIV-1 promoter. This facilitates transcription activation.However, the existence and nature of the putative cellular cofactor involved inthis process still remains open.

Bottom Line: The latency maintenance is also a problematic question.We also describe the differential influence of the HMGA1 protein on the induced and basal transcription of HIV-1.Finally, we offer possible mechanisms for Ku and HMGA1 proteins in the proviral transcription regulation.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Leninskie Gory, Moscow, 119991, Russia.

ABSTRACT
Human immunodeficiency virus type 1 is known to use the transcriptional machinery of the host cell for viral gene transcription, and the only viral protein that partakes in this process is Tat, the viral trans-activator of transcription. During acute infection, the binding of Tat to the hairpin at the beginning of the transcribed viral RNA recruits the PTEFb complex, which in turn hyperphosphorylates RNA-polymerase II and stimulates transcription elongation. Along with acute infection, HIV-1 can also lead to latent infection that is characterized by a low level of viral transcription. During the maintenance and reversal of latency, there are no detectable amounts of Tat protein in the cell and the mechanism of transcription activation in the absence of Tat protein remains unclear. The latency maintenance is also a problematic question. It seems evident that cellular proteins with a yet unknown nature or role regulate both transcriptional repression in the latent phase and its activation during transition into the lytic phase. The present review discusses the role of cellular proteins Ku and HMGA1 in the initiation of transcription elongation of the HIV-1 provirus. The review presents data regarding Ku-mediated HIV-1 transcription and its dependence on the promoter structure and the shape of viral DNA. We also describe the differential influence of the HMGA1 protein on the induced and basal transcription of HIV-1. Finally, we offer possible mechanisms for Ku and HMGA1 proteins in the proviral transcription regulation.

No MeSH data available.


Related in: MedlinePlus