Mini review
The HAT/HDAC interplay: Multilevel control of STAT signaling

https://doi.org/10.1016/j.cytogfr.2012.08.002Get rights and content

Abstract

Besides the transcription-promoting role of histone acetyltransferases (HATs) and the transcription-delimiting function of histone deacetylases (HDACs) through histone acetylation and deacetylation respectively, HATs and HDACs also regulate the activity of several non-histone proteins. This includes signal transducers and activators of transcription (STATs), key proteins in cytokine signaling. Unlike Tyr phosphorylation/dephosphorylation, which mainly acts as an on/off switch of STAT activity, the control exerted by HATs and HDACs appears multifaceted and far more complex than initially imagined. Our review focuses on the latest trends and novel hypotheses to explain differential context-dependent STAT regulation by complex posttranslational modification patterns. We chart the knowledge on how STATs interact with HATs and HDACs, and additionally bring a transcriptional regulatory and gene-set specific role for HDACs in the picture. Indeed, a growing amount of evidence demonstrates, paradoxically, that not only HAT but also HDAC activity can be required for STAT-dependent transcription, in a STAT subtype- and cell type-dependent manner. Referring to recent reports, we review and discuss the various molecular mechanisms that have recently been proposed to account for this peculiar regulation, in an attempt to shed more light on the difficult yet important question on how STAT specificity is being generated.

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)

  • T. Hou et al.

    The STAT3 NH2-terminal domain stabilizes enhanceosome assembly by interacting with the p300 bromodomain

    Journal of Biological Chemistry

    (2008)
  • T. Van Nguyen et al.

    SUMO-specific protease 1 is critical for early lymphoid development through regulation of STAT5 activation

    Molecular Cell

    (2012)
  • P. Shankaranarayanan et al.

    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

    (2001)
  • D. Ungureanu et al.

    SUMO-1 conjugation selectively modulates STAT1-mediated gene responses

    Blood

    (2005)
  • B.A. Benayoun et al.

    A post-translational modification code for transcription factors: sorting through a sea of signals

    Trends in Cell Biology

    (2009)
  • X.J. Yang et al.

    Lysine acetylation: codified crosstalk with other posttranslational modifications

    Molecular Cell

    (2008)
  • J.J. Schuringa et al.

    Ser727-dependent transcriptional activation by association of p300 with STAT3 upon IL-6 stimulation

    FEBS Letters

    (2001)
  • T. Ginter et al.

    Histone deacetylase inhibitors block IFNgamma-induced STAT1 phosphorylation

    Cellular Signalling

    (2012)
  • E.J. Lim et al.

    Epigenetic regulation of the IL-13-induced human eotaxin-3 gene by CREB-binding protein-mediated histone 3 acetylation

    Journal of Biological Chemistry

    (2011)
  • M. Shi et al.

    Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation

    Immunity

    (2008)
  • J. Vlasakova et al.

    Histone deacetylase inhibitors suppress IFNalpha-induced up-regulation of promyelocytic leukemia protein

    Blood

    (2007)
  • S. Sakamoto et al.

    Histone deacetylase activity is required to recruit RNA polymerase II to the promoters of selected interferon-stimulated early response genes

    Journal of Biological Chemistry

    (2004)
  • L. Klampfer et al.

    Requirement of histone deacetylase activity for signaling by STAT1

    Journal of Biological Chemistry

    (2004)
  • Y. Koyama et al.

    Histone deacetylase inhibitors suppress IL-2-mediated gene expression prior to induction of apoptosis

    Blood

    (2000)
  • D. Buglio et al.

    Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines

    Blood

    (2008)
  • T.Y. Lin et al.

    AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated kit

    Blood

    (2010)
  • L. Torres et al.

    In vivo GSH depletion induces c-myc expression by modulation of chromatin protein complexes

    Free Radical Biology and Medicine

    (2009)
  • L. Dong et al.

    PTB-associated splicing factor (PSF) functions as a repressor of STAT6-mediated Ig epsilon gene transcription by recruitment of HDAC1

    Journal of Biological Chemistry

    (2011)
  • R.C. Su et al.

    Epigenetic control of IRF1 responses in HIV-exposed seronegative versus HIV-susceptible individuals

    Blood

    (2011)
  • K.K. Lee et al.

    Histone acetyltransferase complexes: one size doesn’t fit all

    Nature Reviews Molecular Cell Biology

    (2007)
  • M.D. Shahbazian et al.

    Functions of site-specific histone acetylation and deacetylation

    Annual Review of Biochemistry

    (2007)
  • I. Nusinzon et al.

    Histone deacetylases as transcriptional activators? Role reversal in inducible gene regulation

    Science's STKE

    (2005)
  • M. Paulson et al.

    IFN-stimulated transcription through a TBP-free acetyltransferase complex escapes viral shutoff

    Nature Cell Biology

    (2002)
  • E. Korzus et al.

    Transcription factor-specific requirements for coactivators and their acetyltransferase functions

    Science

    (1998)
  • M.M. Brierley et al.

    Stats: multifaceted regulators of transcription

    Journal of Interferon and Cytokine Research

    (2005)
  • J.M. Wojciak et al.

    Structural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domains

    EMBO Journal

    (2009)
  • J.J. Zhang et al.

    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

    (1996)
  • Y.F. Ramos et al.

    Genome-wide assessment of differential roles for p300 and CBP in transcription regulation

    Nucleic Acids Research

    (2010)
  • C. McDonald et al.

    Cooperation of the transcriptional coactivators CBP and p300 with Stat6

    Journal of Interferon and Cytokine Research

    (1999)
  • S. Bhattacharya et al.

    Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha

    Nature

    (1996)
  • S. Ray et al.

    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

    (2002)
  • E. Pfitzner et al.

    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

    (1998)
  • O.H. Kramer et al.

    A phosphorylation–acetylation switch regulates STAT1 signaling

    Genes and Development

    (2009)
  • L. Ma et al.

    Acetylation modulates prolactin receptor dimerization

    Proceedings of the National Academy of Sciences of the United States of America

    (2010)
  • O.H. Kramer et al.

    Acetylation of Stat1 modulates NF-kappaB activity

    Genes and Development

    (2006)
  • E.A. Stronach et al.

    HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer

    Cancer Research

    (2011)
  • 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.

    View full text