Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling

Cao, Wangsen; Bao, Clare; Padalko, Elizaveta; Lowenstein, Charles J.

doi:10.1084/jem.20071728

Cited by 173 publications

(171 citation statements)

References 73 publications

(32 reference statements)

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“…Yersinia YopJ was shown to act as an acetyltransferase to modify serine and threonine residues in the activation loop of MAPK kinase-6, thereby blocking phosphorylation and subsequent activation of the kinase activity (38,39). A nuclearlocalized DUSP1/MKP-1 is acetylated by p300 on Lys57 within its docking domain, resulting in deactivation of Toll-like receptor inflammatory signaling and inhibition of innate immune signaling (22). p300 contains a histone acetyltransferase domain.…”

Section: Discussionmentioning

confidence: 99%

“…The MAPK pathways that mediate innate immune signaling include MAPK kinases 3/4/6, p38, and JNKs (ref. 22 and references therein).…”

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 99%

“…Mtb Eis enhances macrophage survival through the regulation of JNK-dependent ROS signaling (16), whereas DUSP16/MKP-7 works as a JNK-specific phosphatase in vivo (17). Acetylation at Lys57 of DUSP1/MKP-1, a nuclear-localized phosphatase that inactivates MAPK members by dephosphorylation, promoted the interaction of DUSP1/MKP-1 with its substrate p38 MAPK and inhibited innate immune signaling (22,23). Three major subfamilies of MAPKs are ERKs, p38 MAPKs, and JNKs.…”

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 99%

“…We also tested a peptide within the MAPKdocking domain of DUSP1/MKP-1: 50 TIVRRRAKGAMGLE 63 [MKP-1(50−63)] (22). The underlined lysine was established as the acetylation site in the DUSP1/MKP-1 docking domain (22). With these peptides as possible substrates, we performed in vitro acetylation assays using either Mtb Eis or Msm Eis.…”

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 99%

“…Therefore, we examined whether Mtb Eis may acetylate DUSP16/MKP-7, which is known to be a JNK-specific phosphatase (17). We tested a peptide within the MAPK-docking domain of DUSP16/MKP-7: (22). We also tested a peptide within the MAPKdocking domain of DUSP1/MKP-1: 50 TIVRRRAKGAMGLE 63 [MKP-1(50−63)] (22).…”

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 99%

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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

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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...

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Section: Discussionmentioning

confidence: 99%

“…The MAPK pathways that mediate innate immune signaling include MAPK kinases 3/4/6, p38, and JNKs (ref. 22 and references therein).…”

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 99%

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 99%

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 99%

Section: Eis Proteins From Both Mtb and Msm Acetylate Aminoglycosidesmentioning

confidence: 99%

See 3 more Smart Citations

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

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Class I Histone Deacetylase Inhibition Modulates Metalloproteinase Expression and Blocks Cytokine‐Induced Cartilage Degradation

Culley

Wang

Barter

et al. 2013

Arthritis & Rheumatism

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Objective. To examine the ability of a broadspectrum histone deacetylase (HDAC) inhibitor to protect cartilage in vivo, and to explore the effects of class-selective HDAC inhibitors and small interfering RNA (siRNA)-induced knockdown of HDACs on metalloproteinase expression and cartilage degradation in vitro. Cartilage destruction in osteoarthritis (OA) is mediated by the action of proteinases from the matrix metalloproteinase (MMP) and ADAMTS families. The pathology of OA has been proposed to be driven by chondrocytes, because these cells are a major source of MMP expression within the OA joint (1). Metalloproteinase expression is regulated at the transcriptional level, which is in part mediated through changes in protein acetylation catalyzed by enzymes from the histone acetyltransferase and histone deacetylase (HDAC) families. These enzymes not only can modulate the nucleosomal interaction of DNA and histone proteins but also can reversibly acetylate both nuclear and cytoplasmic proteins, with a concomitant change in function (2). Methods. A destabilization of the medial meniscus (DMM) model was used to assess the in vivo activity

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MKP‐1: A critical phosphatase in the biology of macrophages controlling the switch between proliferation and activation

Comalada

Lloberas

2012

Eur J Immunol

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Macrophages play a central role in the immune response. These cells either proliferate in response to, for example, growth factors or become activated in response to, for example, LPS and develop functional activities. Experiments carried out in mice showed that macrophage proliferation requires a short period of ERK phosphorylation, while an extended period is required for macrophage activation. The length of phosphorylation is controlled by the MAPK phosphatase-1 (MKP-1), a nuclear-localized dual-specificity phosphatase that dephosphorylates the MAPKs ERK, p38, and c-Jun NH 2 -terminal kinase (JNK). MKP-1 is induced in macrophages by growth factors, as well as by activators such as LPS, but with different kinetics; to achieve the different functional outcomes (proliferation versus activation), the inhibition of MKP-1 by cytokines such as IFN-γ blocks macrophage proliferation and induces activation. The data presented in this review show that this phosphatase is the switch between macrophage proliferation and activation. Keywords: Inflammation r Innate immunity r Kinases r Macrophages r Signal transduction IntroductionMonocytes/macrophages perform essential functions in homeostasis, infection, tissue repair, and resolution of inflammation [1][2][3]. These cells have pleiotropic functions in the body and not only do they play a key role in the immune system, but they are also critical for the homeostasis of a number of metabolic systems. For example, aged red blood cells display several modifications in their membranes that macrophages recognize and use to phagocytose and eliminate these cells. By doing so, macrophages obtain iron from hemoglobin and are able to release it at a later time point depending on the body's requirements. Thus, iron metabolism is controlled mostly by macrophages [4].Correspondence: Prof. Antonio Celada e-mail: acelada@ub.edu Concerning the immune system, macrophages participate in both innate and acquired immune responses. Therefore, these cells play a critical role in host-defense mechanisms. Monocytes originate from bone marrow undifferentiated stem cells in response to specific growth factors such as M-CSF, IL-3, and GM-CSF [5] and they reach all the tissues in the body via the blood system [6]. In response to the growth factors and cytokines with which they interact, macrophages may proliferate and differentiate to specific cell types depending on the tissue (in the brain to microglia; in the bone to osteoclasts; in the liver to Kupffer cells; in the skin to Langerhans cells; in the bone to bone marrow macrophages; and in the intestine to crypt macrophages), or they become activated and develop their functional activities.In 1976, the first hematopoietic growth factor, M-CSF (also referred to as CSF-1 at that time), was isolated, which facilitated studies on macrophage proliferation since M-CSF has the capacity to induce the growth of pure colonies of macrophages from bone marrow progenitors in vitro [7]. In 1985, it was found that M-CSF interacts with a tyrosine kinase receptor me...

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Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling

Cited by 173 publications

References 73 publications

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

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

Class I Histone Deacetylase Inhibition Modulates Metalloproteinase Expression and Blocks Cytokine‐Induced Cartilage Degradation

MKP‐1: A critical phosphatase in the biology of macrophages controlling the switch between proliferation and activation

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