The integration of viral cDNA into the host genome is a critical step in the life cycle of HIV-1. This step is catalyzed by integrase (IN), a viral enzyme that is positively regulated by acetylation via the cellular histone acetyl transferase (HAT) p300. To investigate the relevance of IN acetylation, we searched for cellular proteins that selectively bind acetylated IN and identified KAP1, a protein belonging to the TRIM family of antiviral proteins. KAP1 binds acetylated IN and induces its deacetylation through the formation of a protein complex which includes the deacetylase HDAC1. Modulation of intracellular KAP1 levels in different cell types including T cells, the primary HIV-1 target, revealed that KAP1 curtails viral infectivity by selectively affecting HIV-1 integration. This study identifies KAP1 as a cellular factor restricting HIV-1 infection and underscores the relevance of IN acetylation as a crucial step in the viral infectious cycle.
Protein interactions
| Protein | Gene | Interaction | Pubs |
|---|---|---|---|
| Envelope surface glycoprotein gp120 | env | Tandem affinity purification and mass spectrometry analysis identify tripartite motif containing 28 (TRIM28), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells | PubMed |
| Gag-Pol | gag-pol | Tandem affinity purification and mass spectrometry analysis identify tripartite motif containing 28 (TRIM28), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells | PubMed |
| Nef | nef | Tandem affinity purification and mass spectrometry analysis identify tripartite motif containing 28 (TRIM28), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells | PubMed |
| Pr55(Gag) | gag | Tandem affinity purification and mass spectrometry analysis identify tripartite motif containing 28 (TRIM28), HIV-1 Gag, Gag/Pol, gp120, and Nef incorporated into staufen1 RNP complexes isolated from HIV-1-expressing cells | PubMed |
| integrase | gag-pol | KAP1 inhibits HIV-1 integration via HIV-1 IN acetylation-dependent mechanism through HDAC1 | PubMed |
| gag-pol | The interaction between HIV-1 IN and KAP1 is highly favored by HAT/p300-mediated IN acetylation | PubMed |
Go to the HIV-1, Human Interaction Database
HIV_1 integraasin inhibiittoreita on kehitelty.
HIV_1 integraasin inhibiittoreita on kehitelty.
2016: Progress in HIV-1 Integrase Inhibitors: A Review of their Chemical Structure Diversity
Author information Article notes Copyright and License information Disclaimer
HIV-1 integrase (IN) enzyme,
one of the three main enzymes of HIV-1, catalyzed the insertion of the
viral DNA into the genome of host cells. Because of the lack of its
homologue in human cells and its essential role in HIV-1 replication, IN
inhibition represents an attractive therapeutic target for HIV-1
treatment. Since identification of IN as a promising therapeutic target,
a major progress has been made, which has facilitated and led to the
approval of three drugs. This review focused on the structural features
of the most important IN inhibitors and categorized them structurally in
10 scaffolds. We also briefly discussed the structural and functional
properties of HIV-1 IN and binding modes of IN inhibitors. The SAR
analysis of the known IN inhibitors provides some useful clues to the
possible future discovery of novel IN inhibitors.
Key Words: HIV-1, Integrase enzyme, SAR, Molecular diversity, IN Inhibitors
IN inhibitors are consisting of two main
classes: integrase strand transfer inhibitors (INSTIs) and
protein–protein interaction inhibitors (PPIIs). INSTIs target the enzyme
active site, and the FDA-approved IN inhibitors are all INSTIs. IN
catalyzes the incorporation of viral DNA into the host chromatin on
interactions with various cellular proteins, such as lens
epithelium-derived growth factor (LEDGF)/p75. LEDGINs which act as
inhibitors of the LEDGF/p75–integrase interaction have been
substantially developed in recent years (8-12).
In
this review, we provided an insight to the structure and function of
HIV-1 IN and its role in HIV-1 replication. We also highlighted progress
medicinal chemistry efforts have made to date on IN inhibitors.
IN inhibitors are consisting of two main
classes: integrase strand transfer inhibitors (INSTIs) and
protein–protein interaction inhibitors (PPIIs). INSTIs target the enzyme
active site, and the FDA-approved IN inhibitors are all INSTIs. IN
catalyzes the incorporation of viral DNA into the host chromatin on
interactions with various cellular proteins, such as lens
epithelium-derived growth factor (LEDGF)/p75. LEDGINs which act as
inhibitors of the LEDGF/p75–integrase interaction have been
substantially developed in recent years (8-12).
In
this review, we provided an insight to the structure and function of
HIV-1 IN and its role in HIV-1 replication. We also highlighted progress
medicinal chemistry efforts have made to date on IN inhibitors.
HIV-1 retroviral replication cycle (derived from 22).
PMC full text:
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- KAP1 trim28 PROTEIINIIN VAIIKUTTAA myös sirtuiinin DEASEYLAATIOFUNKTIO.
- .
PLoS One. 2015 Apr 23;10(4):e0123935. doi: 10.1371/journal.pone.0123935. eCollection 2015.
KAP1 Deacetylation by SIRT1 Promotes Non-Homologous End-Joining Repair.
Abstract
Homologous
recombination and non-homologous end joining are two major DNA
double-strand-break repair pathways. While HR-mediated repair requires a
homologous sequence as the guiding template to restore the damage site
precisely, NHEJ-mediated repair ligates the DNA lesion directly and
increases the risk of losing nucleotides. Therefore, how a cell
regulates the balance between HR and NHEJ has become an important issue
for maintaining genomic integrity over time. Here we report that
SIRT1-dependent KAP1 deacetylation positively regulates NHEJ. We show
that up-regulation of KAP1 attenuates HR efficiency while promoting NHEJ
repair. Moreover, SIRT1-mediated KAP1 deacetylation further enhances
the effect of NHEJ by stabilizing its interaction with 53BP1, which
leads to increased 53BP1 focus formation in response to DNA damage.
Taken together, our study suggests a SIRT1-KAP1 regulatory mechanism for
HR-NHEJ repair pathway choice. PMID: 25905708 PMCID:PMC4408008 DOI: 10.1371/journal.pone.0123935[Indexed for MEDLINE]Free PMC Article
Curr Drug Targets. 2013 Jun 1;14(6):648-52.
Sirtuin-1 and HIV-1: an overview.
Abstract
Sirtuins
are a family of NAD+-dependent protein deacetylases, which regulate
cell survival and energy metabolism, inflammation and cancer. Recent
studies have shown that sirtuin-1 (SIRT1) modulates Human
Immunodeficiency Virus (HIV)-1 transcription. The HIV-1 Tat protein is a
substrate for the deacetylase activity of SIRT1; SIRT1 recycles Tat to
its unacetylated form, catalyzing a fundamental step to start new cycles
of viral transcription. Moreover, Tat has been reported to promote
T-cell hyperactivation by suppressing SIRT1 activity. In fact, Tat
blocks the ability of SIRT1 to deacetylate lysine 310 in the p65 subunit
of nuclear factor- κB (NF- κB) by interacting with the deacetylase
domain of SIRT1. This mechanism leads therefore to the hyperactivation
of NF- κB proinflammatory pathway and may likely contribute to the
chronic immune activation state of HIV-infected individuals. In the
present review we first briefly describe the biological functions of
sirtuins, then we delineate the interplay between SIRT1 and HIV-1 and
discuss the potential role of SIRT1 as a pharmacological target of HIV-1
replication.
- PMID:
- 23547809
- [Indexed for MEDLINE]
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