Mini reviewThe HAT/HDAC interplay: Multilevel control of STAT signaling
Introduction
Twenty years after its discovery, STAT-dependent signaling is now one of the best studied signal transduction pathways. The binding of cytokines and growth factors to their cognate receptors differentially activates 7 STAT proteins (STAT1–4, STAT5A, STAT5B and STAT6), which in turn regulate the expression of genes involved in cell homeostasis, growth, differentiation, apoptosis and immune response [1]. The structure of STAT proteins consists of 6 conserved domains, including an amino-terminal (NH2) and a coiled-coil (CC) domain, a DNA-binding domain (DBD), a linker, a Src Homology (SH)2 and a transactivation domain (TAD) (Fig. 1A). Like every signaling cascade in eukaryotic organisms, the STAT pathway is tightly regulated by several posttranslational modifications (PTMs), which affect different signaling events from the receptor level down, ultimately modulating the enhanceosome formation at the promoter of target genes. The major advantage of this regulation is its rapid and dynamic nature: PTMs may be added within minutes from stimulation and are promptly removed by enzymes with opposed functions, resetting the activity of the target protein and rendering it available for the next activation cycle. STAT activity is regulated by a stimulus-induced phosphorylation on hallmark tyrosine and serine residues in the TAD, which generally correlates with transcriptionally active STATs. Nevertheless, evidence has emerged revealing that STAT phosphorylation and STAT activity may be uncoupled and that STAT signaling is modulated by the interplay between several other posttranslational modifications [1].
Acetylation is mediated by histone acetyltransferases (HATs), which catalyze the transfer of acetyl groups to the ɛ-amino group of lysine (Lys or K) residues. HAT enzymes are organized in 3 major groups: the GCN5-related N-acetyltransferases (GNATs), the E1A-associated protein of 300 kDa (p300)/CREB-binding protein (CBP) and MYST proteins [2]. The N-terminal tails of histones were the first identified substrates of HATs: acetylation masks the positive charges present on the lysine residues, reducing the affinity between histones and negatively charged DNA, thereby facilitating the recruitment of transcriptional co-activators [3]. HAT activity is reverted by histone deacetylases (HDACs), which contain deacetylase catalytic domains responsible for the removal of the acetyl groups, tightening the interaction between DNA and histones and repressing transcription. HDACs are organized in four classes depending on sequence identity and domain organization. Class I (HDAC1, 2, 3 and 8), class II (HDAC4, 5, 6, 7, 9 and 10) and class IV (HDAC11) are zinc-dependent HDACs, while class III (SIRT1–7) deacetylases are NAD+-dependent [4].
It is now clear that also non-histone proteins may be acetylated or deacetylated, including several transcription factors [5]. Because HATs and HDACs often function within the context of transcriptional activator and repressor complexes respectively, acetylation is generally linked to transcriptional activation and deacetylation to transcriptional repression. Increasing evidence, however, indicates that the regulation of protein activity and gene transcription by acetylation is more dynamic and complex than a simple on/off switch, and that HATs and HDACs may have non-canonical functions, in which acetylation downregulates transcription, and HDAC activity is required for transcriptional activation [6]. In this review, we discuss in detail the emerging role of acetylation and deacetylation processes in STAT signal transduction and the implication hereof for STAT-dependent (patho)physiology. We discuss the role of HATs and HDACs to regulate STAT signaling and we highlight recently unraveled mechanisms of transcriptional regulation that potentially contribute in generating STAT-specific gene programs.
Section snippets
HAT activity is required for STAT-dependent signaling
STAT proteins have been described to associate with several HATs, including the E1A binding protein p300 and the structurally related cAMP-response element binding (CREB)-binding protein (CBP) as well as the lysine acetyltransferase 2A (KAT2A, aka GCN5) and 2B (KAT2B, aka P/CAF) [7], [8]. All seven STAT members have been described to interact with p300/CBP through their C-terminal TADs, despite the fact that this domain is relatively poorly conserved among STAT proteins [9], [10]. In addition,
Requirement of HDAC activity in STAT-dependent signaling
HDAC activity is normally associated with transcriptional repression, as histone deacetylation tightens the chromatin structure and impairs the assembly of the enhanceosome. STAT proteins can directly interact with HDACs and treatment with HDACi leads to STAT hyperacetylation. Given the importance of acetylation for several steps of STAT-dependent signaling, it seems reasonable to expect HDACs to exert a negative regulation on STAT activity. However, several reports indicate that HDAC activity
STAT acetylation/deacetylation and cross-talk with heterologous pathways
The role of acetylation in regulating STAT activity opens new possibilities of crosstalk with heterologous signaling pathways. For example, LIF or IL-6 triggered acetylation of Lys685 on STAT3 was reported to depend on the PI3K/Akt pathway, since cell treatment with the PI3K inhibitor LY294002 strongly affected acetylation [49]. In addition, it was previously shown that CD44, a transmembrane glycoprotein recently recognized as a signature for cancer stem cells, may translocate to the nucleus
Conclusion
A vast number of cytokine, growth factor and hormone receptors signal through STATs to orchestrate a broad range of cellular and physiological responses, including host defense, metabolic regulation, inflammation and cancer development. The JAK/STAT cascade is one of the most conserved metazoan signaling pathways. It appears a simple cascade, composed by a limited combination of 4 different JAK molecules and 7 STATs in human. The molecular mechanisms that allow this relative small number of
Laura Icardi graduated in Molecular Biotechnology in 2006 in the University of Turin, Italy, working as an undergraduate student on the cross-talk between STAT1 and STAT3 in type II interferon signaling and its impact on cancer growth. In 2007, she joined the CRL as a PhD student, in the contest of the Marie Curie ReceptEUR network. Her PhD thesis focused on the role of acetylation and deacetylation processes on STAT signal transduction.
References (93)
- et al.
The JAK–STAT pathway at twenty
Immunity
(2012) - et al.
Histone/protein deacetylases and T-cell immune responses
Blood
(2012) - et al.
Acetylation of non-histone proteins modulates cellular signalling at multiple levels
International Journal of Biochemistry and Cell Biology
(2009) - et al.
Acetylation-dependent signal transduction for type I interferon receptor
Cell
(2007) Chromatin modifications and their function
Cell
(2007)- et al.
p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages
Blood
(2011) - et al.
Stat1 acetylation inhibits inducible nitric oxide synthase expression in interferon-gamma-treated RAW264.7 murine macrophages
Surgery
(2007) - et al.
Phosphorylation–acetylation switch in the regulation of STAT1 signaling
Molecular and Cellular Endocrinology
(2010) - et al.
Activation of Stat3 sequence-specific DNA binding and transcription by p300/CREB-binding protein-mediated acetylation
Journal of Biological Chemistry
(2005) - et al.
STAT3 NH2-terminal acetylation is activated by the hepatic acute-phase response and required for IL-6 induction of angiotensinogen
Gastroenterology
(2005)
The STAT3 NH2-terminal domain stabilizes enhanceosome assembly by interacting with the p300 bromodomain
Journal of Biological Chemistry
SUMO-specific protease 1 is critical for early lymphoid development through regulation of STAT5 activation
Molecular Cell
Acetylation by histone acetyltransferase CREB-binding protein/p300 of STAT6 is required for transcriptional activation of the 15-lipoxygenase-1 gene
Journal of Biological Chemistry
SUMO-1 conjugation selectively modulates STAT1-mediated gene responses
Blood
A post-translational modification code for transcription factors: sorting through a sea of signals
Trends in Cell Biology
Lysine acetylation: codified crosstalk with other posttranslational modifications
Molecular Cell
Ser727-dependent transcriptional activation by association of p300 with STAT3 upon IL-6 stimulation
FEBS Letters
Histone deacetylase inhibitors block IFNgamma-induced STAT1 phosphorylation
Cellular Signalling
Epigenetic regulation of the IL-13-induced human eotaxin-3 gene by CREB-binding protein-mediated histone 3 acetylation
Journal of Biological Chemistry
Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation
Immunity
Histone deacetylase inhibitors suppress IFNalpha-induced up-regulation of promyelocytic leukemia protein
Blood
Histone deacetylase activity is required to recruit RNA polymerase II to the promoters of selected interferon-stimulated early response genes
Journal of Biological Chemistry
Requirement of histone deacetylase activity for signaling by STAT1
Journal of Biological Chemistry
Histone deacetylase inhibitors suppress IL-2-mediated gene expression prior to induction of apoptosis
Blood
Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines
Blood
AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated kit
Blood
In vivo GSH depletion induces c-myc expression by modulation of chromatin protein complexes
Free Radical Biology and Medicine
PTB-associated splicing factor (PSF) functions as a repressor of STAT6-mediated Ig epsilon gene transcription by recruitment of HDAC1
Journal of Biological Chemistry
Epigenetic control of IRF1 responses in HIV-exposed seronegative versus HIV-susceptible individuals
Blood
Histone acetyltransferase complexes: one size doesn’t fit all
Nature Reviews Molecular Cell Biology
Functions of site-specific histone acetylation and deacetylation
Annual Review of Biochemistry
Histone deacetylases as transcriptional activators? Role reversal in inducible gene regulation
Science's STKE
IFN-stimulated transcription through a TBP-free acetyltransferase complex escapes viral shutoff
Nature Cell Biology
Transcription factor-specific requirements for coactivators and their acetyltransferase functions
Science
Stats: multifaceted regulators of transcription
Journal of Interferon and Cytokine Research
Structural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domains
EMBO Journal
Two contact regions between Stat1 and CBP/p300 in interferon gamma signaling
Proceedings of the National Academy of Sciences of the United States of America
Genome-wide assessment of differential roles for p300 and CBP in transcription regulation
Nucleic Acids Research
Cooperation of the transcriptional coactivators CBP and p300 with Stat6
Journal of Interferon and Cytokine Research
Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha
Nature
Angiotensinogen gene expression is dependent on signal transducer and activator of transcription 3-mediated p300/cAMP response element binding protein-binding protein coactivator recruitment and histone acetyltransferase activity
Molecular Endocrinology
p300/CREB-binding protein enhances the prolactin-mediated transcriptional induction through direct interaction with the transactivation domain of Stat5, but does not participate in the Stat5-mediated suppression of the glucocorticoid response
Molecular Endocrinology
A phosphorylation–acetylation switch regulates STAT1 signaling
Genes and Development
Acetylation modulates prolactin receptor dimerization
Proceedings of the National Academy of Sciences of the United States of America
Acetylation of Stat1 modulates NF-kappaB activity
Genes and Development
HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer
Cancer Research
Cited by (0)
Laura Icardi graduated in Molecular Biotechnology in 2006 in the University of Turin, Italy, working as an undergraduate student on the cross-talk between STAT1 and STAT3 in type II interferon signaling and its impact on cancer growth. In 2007, she joined the CRL as a PhD student, in the contest of the Marie Curie ReceptEUR network. Her PhD thesis focused on the role of acetylation and deacetylation processes on STAT signal transduction.
Karolien De Bosscher graduated as a biochemist in 1995 and obtained her PhD at UGent on the molecular mechanisms of glucocorticoids in 2000. Next, she studied TGFβ-signaling pathways at the Cancer Research UK institute in London. From 2003 onwards she has been supported by FWO-Vlaanderen, enabling her to guide the Nuclear Receptor Signaling Unit at the UGent LEGEST lab. In 2010 she joined CRL, where she continues to study transcription factor-mediated gene activation and repression mechanisms.
Jan Tavernier founded the Cytokine Receptor Laboratory (CRL) in 1996. He obtained his PhD in 1984 in the early days of recombinant DNA on the cloning of several interferon and interleukin genes. In the same year he moved to industry, first Biogen, later Roche, where he continued cytokine research and demonstrated for the first time the shared use of cytokine receptor subunits. He became full professor at Ghent University in 1996 and currently heads the CRL as part of the VIB Department of Medical Protein Research.