The emerging role of lysine acetylation of non-nuclear proteins

Close, Pierre; Creppe, Catherine; Gillard, Magali; Ladang, Aurélie; Chapelle, Jean-Paul; Nguyen, Laurent; Chariot, Alain

doi:10.1007/s00018-009-0252-7

Cited by 70 publications

(54 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, reversible protein lysine acetylation has also been demonstrated to be a common PTM of non-nuclear proteins. 17 As GIP and GLP-1 were both shown to be capable of stimulating histone acetylation, 18 the effects of these incretins on levels of phosphorylated and acetylated Kv2.1 were examined. Transfected INS-1 b-cells were treated with GIP or GLP-1 and solubilized extracts immunoprecipitated with phosphoserine/threonine or acetyl-lysine antibodies, followed by immunoblotting with Kv2.1 antibody.…”

Section: Resultsmentioning

confidence: 99%

Pancreatic β-cell prosurvival effects of the incretin hormones involve post-translational modification of Kv2.1 delayed rectifier channels

Widenmaier

Choi

et al. 2011

Cell Death Differ

View full text Add to dashboard Cite

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the major incretin hormones that exert insulinotropic and anti-apoptotic actions on pancreatic b-cells. Insulinotropic actions of the incretins involve modulation of voltage-gated potassium (Kv) channels. In multiple cell types, Kv channel activity has been implicated in cell volume changes accompanying initiation of the apoptotic program. Focusing on Kv2.1, we examined whether regulation of Kv channels in b-cells contributes to the prosurvival effects of incretins. Overexpression of Kv2.1 in INS-1 b-cells potentiated apoptosis in response to mitochondrial and ER stress and, conversely, co-stimulation with GIP/GLP-1 uncoupled this potentiation, suppressing apoptosis. In parallel, incretins promoted phosphorylation and acetylation of Kv2.1 via pathways involving protein kinase A (PKA)/mitogen-and stress-activated kinase-1 (MSK-1) and histone acetyltransferase (HAT)/histone deacetylase (HDAC). Further studies demonstrated that acetylation of Kv2.1 was mediated by incretin actions on nuclear/cytoplasmic shuttling of CREB binding protein (CBP) and its interaction with Kv2.1. Regulation of b-cell survival by GIP and GLP-1 therefore involves posttranslational modifications (PTMs) of Kv channels by PKA/MSK-1 and HAT/HDAC. This appears to be the first demonstration of modulation of delayed rectifier Kv channels contributing to the b-cell prosurvival effects of incretins and of 7-transmembrane G protein-coupled receptor (GPCR)-stimulated export of a nuclear lysine acetyltransferase that regulates cell surface ion channel function.

show abstract

Section: Resultsmentioning

confidence: 99%

Pancreatic β-cell prosurvival effects of the incretin hormones involve post-translational modification of Kv2.1 delayed rectifier channels

Widenmaier

Choi

et al. 2011

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…It has been well established that protein lysine acetylation critically regulates gene transcription by targeting histones as well as a variety of transcription factors in the nucleus (40). Numerous proteins located outside the nucleus have also been demonstrated to be acetylated (40).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Numerous proteins located outside the nucleus have also been demonstrated to be acetylated (40). Indeed, protein lysine acetylation is emerging as a major mechanism by which key proteins are regulated in many physiological processes (40). Recent reports also link lysine acetylation to heterochromatin assembly, sister chromatid cohesion, cytoskeleton dynamics, autophagy, receptor signaling, RNA processing, and metabolic control (41).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

Kim¹,

Song³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

171

152

View full text Add to dashboard Cite

The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes tuberculosis. Enhanced intracellular survival (Eis) protein, secreted by Mtb, enhances survival of Mycobacterium smegmatis (Msm) in macrophages. Mtb Eis was shown to suppress host immune defenses by negatively modulating autophagy, inflammation, and cell death through JNK-dependent inhibition of reactive oxygen species (ROS) generation. Mtb Eis was recently demonstrated to contribute to drug resistance by acetylating multiple amines of aminoglycosides. However, the mechanism of enhanced intracellular survival by Mtb Eis remains unanswered. Therefore, we have characterized both Mtb and Msm Eis proteins biochemically and structurally. We have discovered that Mtb Eis is an efficient N ɛ -acetyltransferase, rapidly acetylating Lys55 of dualspecificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7), a JNK-specific phosphatase. In contrast, Msm Eis is more efficient as an N α -acetyltransferase. We also show that Msm Eis acetylates aminoglycosides as readily as Mtb Eis. Furthermore, Mtb Eis, but not Msm Eis, inhibits LPSinduced JNK phosphorylation. This functional difference against DUSP16/MKP-7 can be understood by comparing the structures of two Eis proteins. The active site of Mtb Eis with a narrow channel seems more suitable for sequence-specific recognition of the protein substrate than the pocket-shaped active site of Msm Eis. We propose that Mtb Eis initiates the inhibition of JNK-dependent autophagy, phagosome maturation, and ROS generation by acetylating DUSP16/MKP-7. Our work thus provides insight into the mechanism of suppressing host immune responses and enhancing mycobacterial survival within macrophages by Mtb Eis.Rv2416c | lysine acetylation | antituberculosis drug N early one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb). This pathogenic bacterium causes tuberculosis, which claims the lives of millions of people every year (1). Tuberculosis has also become a global health issue owing to the increased incidences of multidrug-resistant and extensively drug-resistant strains of Mtb (2). This makes a search for targets of new antituberculosis drugs urgent. Mtb is a highly successful human pathogen, surviving and multiplying within the human macrophage cells of the infected people (3). Therefore, treatment of tuberculosis is difficult, requiring many months of taking a combination of antibiotics. Mtb has the ability to persist in the form of a long-term asymptomatic infection, referred to as latent tuberculosis (4). Latent tuberculosis becomes activated when the body's immune system is weakened. As a result, tuberculosis is the major cause of death among immuno-compromised AIDS patients (5).In mycobacterial infection, host innate immune responses may play a crucial role in early protection against Mtb infection, leading to establishment of effective adaptive immunity to tuberculosis (6). Additionally, MAPK pathways are activated by Mtb or its components and play an e...

show abstract

“…For example, phosphorylation of residues in or near NLS sequences commonly alters their function (Moll et al, 1991;Rihs et al, 1991). In addition, acetylation of lysine residues within an NLS can inhibit their function, as addition of neutral acetyl groups to the e-amino group of lysine residues negates their positive charge (Close et al, 2010;Yang, 2004). A prominent example is the tyrosine kinase c-Abl, which is blocked from entering the nucleus by acetylation of residues in its NLS sequence (Dietschy et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Acetylation of the RhoA GEF Net1A controls its subcellular localization and activity

Song

Ulu

et al. 2015

Journal of Cell Science

View full text Add to dashboard Cite

Net1 isoform A (Net1A) is a RhoA GEF that is required for cell motility and invasion in multiple cancers. Nuclear localization of Net1A negatively regulates its activity, and we have recently shown that Rac1 stimulates Net1A relocalization to the plasma membrane to promote RhoA activation and cytoskeletal reorganization. However, mechanisms controlling the subcellular localization of Net1A are not well understood. Here, we show that Net1A contains two nuclear localization signal (NLS) sequences within its Nterminus and that residues surrounding the second NLS sequence are acetylated. Treatment of cells with deacetylase inhibitors or expression of active Rac1 promotes Net1A acetylation. Deacetylase inhibition is sufficient for Net1A relocalization outside the nucleus, and replacement of the N-terminal acetylation sites with arginine residues prevents cytoplasmic accumulation of Net1A caused by deacetylase inhibition or EGF stimulation. By contrast, replacement of these sites with glutamine residues is sufficient for Net1A relocalization, RhoA activation and downstream signaling. Moreover, the N-terminal acetylation sites are required for rescue of F-actin accumulation and focal adhesion maturation in Net1 knockout MEFs. These data indicate that Net1A acetylation regulates its subcellular localization to impact on RhoA activity and actin cytoskeletal organization.

show abstract

The emerging role of lysine acetylation of non-nuclear proteins

Cited by 70 publications

References 98 publications

Pancreatic β-cell prosurvival effects of the incretin hormones involve post-translational modification of Kv2.1 delayed rectifier channels

Pancreatic β-cell prosurvival effects of the incretin hormones involve post-translational modification of Kv2.1 delayed rectifier channels

Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

Acetylation of the RhoA GEF Net1A controls its subcellular localization and activity

Contact Info

Product

Resources

About