SARS-CoV-2 hijacks p38β/MAPK11 to promote viral protein translation

SARS-CoV-2, the causative agent of the COVID-19 pandemic, drastically modifies the cells that it infects. One such effect is the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammation pathways that are dysregulated in severe COVID-19 cases. Inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduces both cytokine production and viral replication. Here, we applied a systems biology approach to better understand interactions between the p38/MAPK pathway and SARS-CoV-2 in human lung epithelial cells. We found several components of the p38/MAPK pathway positively and negatively impact SARS-CoV-2 infection and that p38β is a required host factor for SARS-CoV-2 that acts by promoting viral protein translation in a manner that prevents innate immune sensing. Furthermore, we combined chemical and genetic perturbations of p38β with quantitative phosphoproteomics to identify novel, putative p38β substrates in an unbiased manner, with broad relevance beyond SARS-CoV-2 biology.

Download Full-text

Somatostatin stimulates intestinal NHE8 expression via p38 MAPK pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00421.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. C375-C382 ◽

Cited By ~ 15

Author(s):

Chunhui Wang ◽

Hua Xu ◽

Huacong Chen ◽

Jing Li ◽

Bo Zhang ◽

...

Keyword(s):

P38 Mapk ◽

Mapk Pathway ◽

Somatostatin Receptor ◽

Peptide Hormone ◽

Mitogen Activated Protein Kinase ◽

Mapk Phosphorylation ◽

P38 Mapk Pathway ◽

Mitogen Activated Protein ◽

D Cells ◽

Human Intestinal Cells

Diarrhea is a common manifestation of gastrointestinal disorders. Diarrhea-induced losses of fluid and electrolyte could lead to dehydration and electrolyte imbalances, resulting in significant morbidity and mortality, especially in children living in developing countries. Somatostatin, a peptide hormone secreted by D-cells, plays an important role in regulating motility and intestinal Na+ absorption. Although octreotide, a somatostatin analog, is used to treat diarrhea, its mechanisms of action are unclear. Here we showed that octreotide increased brush-border membrane Na+/H+ exchanger 8 (NHE8) expression in the small intestine to the exclusion of other NHEs that participate in Na+ absorption. The same effect also occurred in human intestinal cells (Caco-2). We found that the increase of NHE8 expression by somatostatin required p38 mitogen-activated protein kinase (MAPK) activation. Furthermore, the somatostatin receptor SSTR2 antagonist CYN154806 could abolish somatostatin-induced NHE8 expression and p38 MAPK phosphorylation. Thus our data provided the first concrete evidence indicating that somatostatin stimulates intestinal Na+ absorption by increasing intestinal NHE8 expression through the SSTR2-p38 MAPK pathway.

Download Full-text

APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00427.2010 ◽

2011 ◽

Vol 300 (1) ◽

pp. E103-E110 ◽

Cited By ~ 59

Author(s):

Xiaoban Xin ◽

Lijun Zhou ◽

Caleb M. Reyes ◽

Feng Liu ◽

Lily Q. Dong

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Mapk Pathway ◽

Adaptor Protein ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Scaffolding Protein ◽

Mapk Activation ◽

P38 Mapk Pathway ◽

Mitogen Activated Protein

The adaptor protein APPL1 mediates the stimulatory effect of adiponectin on p38 mitogen-activated protein kinase (MAPK) signaling, yet the underlying mechanism remains unclear. Here we show that, in C2C12 cells, overexpression or suppression of APPL1 enhanced or suppressed, respectively, adiponectin-stimulated p38 MAPK upstream kinase cascade, consisting of transforming growth factor-β-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase 3 (MKK3). In vitro affinity binding and coimmunoprecipitation experiments revealed that TAK1 and MKK3 bind to different regions of APPL1, suggesting that APPL1 functions as a scaffolding protein to facilitate adiponectin-stimulated p38 MAPK activation. Interestingly, suppressing APPL1 had no effect on TNFα-stimulated p38 MAPK phosphorylation in C2C12 myotubes, indicating that the stimulatory effect of APPL1 on p38 MAPK activation is selective. Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation.

Download Full-text

Posttranslational Regulation of Tristetraprolin Subcellular Localization and Protein Stability by p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Regulated Kinase Pathways

Molecular and Cellular Biology ◽

10.1128/mcb.26.6.2408-2418.2006 ◽

2006 ◽

Vol 26 (6) ◽

pp. 2408-2418 ◽

Cited By ~ 187

Author(s):

Matthew Brook ◽

Carmen R. Tchen ◽

Tomas Santalucia ◽

Joanne McIlrath ◽

J. Simon C. Arthur ◽

...

Keyword(s):

Protein Kinase ◽

Subcellular Localization ◽

Protein Stability ◽

P38 Mapk ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signal Regulated Kinase ◽

P38 Mapk Pathway ◽

Extracellular Signal ◽

Mitogen Activated Protein

ABSTRACT The p38 mitogen-activated protein kinase (MAPK) signaling pathway, acting through the downstream kinase MK2, regulates the stability of many proinflammatory mRNAs that contain adenosine/uridine-rich elements (AREs). It is thought to do this by modulating the expression or activity of ARE-binding proteins that regulate mRNA turnover. MK2 phosphorylates the ARE-binding and mRNA-destabilizing protein tristetraprolin (TTP) at serines 52 and 178. Here we show that the p38 MAPK pathway regulates the subcellular localization and stability of TTP protein. A p38 MAPK inhibitor causes rapid dephosphorylation of TTP, relocalization from the cytoplasm to the nucleus, and degradation by the 20S/26S proteasome. Hence, continuous activity of the p38 MAPK pathway is required to maintain the phosphorylation status, cytoplasmic localization, and stability of TTP protein. The regulation of both subcellular localization and protein stability is dependent on MK2 and on the integrity of serines 52 and 178. Furthermore, the extracellular signal-regulated kinase (ERK) pathway synergizes with the p38 MAPK pathway to regulate both stability and localization of TTP. This effect is independent of kinases that are known to be synergistically activated by ERK and p38 MAPK. We present a model for the actions of TTP and the p38 MAPK pathway during distinct phases of the inflammatory response.

Download Full-text

Modulation of the p38 MAPK (mitogen-activated protein kinase) pathway through Bcr/Abl: implications in the cellular response to Ara-C

Biochemical Journal ◽

10.1042/bj20040927 ◽

2005 ◽

Vol 387 (1) ◽

pp. 231-238 ◽

Cited By ~ 17

Author(s):

Víctor Javier SÁNCHEZ-ARÉVALO LOBO ◽

Clara Isabel ACEVES LUQUERO ◽

Luis ÁLVAREZ-VALLINA ◽

Alex J. TIPPING ◽

Juan Guinea VINIEGRA ◽

...

Keyword(s):

Protein Kinase ◽

Chronic Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

P38 Mapk ◽

Cellular Response ◽

Mapk Pathway ◽

K562 Cells ◽

Mitogen Activated Protein Kinase ◽

P38 Mapk Pathway ◽

Mitogen Activated Protein

The chimaeric protein Bcr/Abl, the hallmark of chronic myeloid leukaemia, has been connected with several signalling pathways, such as those involving protein kinase B/Akt, JNK (c-Jun N-terminal kinase) or ERKs (extracellular-signal-regulated kinases) 1 and 2. However, no data about the p38 MAPK (mitogen-activated protein kinase) have been reported. Here, we present evidence showing that Bcr/Abl is able to modulate this signalling pathway. Transient transfection experiments indicated that overexpression of Bcr/Abl in 293T cells is able to activate p38 MAPK or induce p73 stabilization, suggesting that c-Abl and Bcr/Abl share some biological substrates. Interestingly, the control exerted by Bcr/Abl on the p38 MAPK pathway was not only mediated by the tyrosine kinase activity of Bcr/Abl, as the use of STI571 demonstrated. In fact, Bcr alone was able to induce p38 MAPK activation specifically through MKK3 (MAP kinase kinase 3). Supporting these observations, chronic myeloid leukaemia-derived K562 cells or BaF 3 cells stably transfected with Bcr/Abl showed higher levels of phosphorylated p38 MAPK compared with Bcr/Abl-negative cells. While Bcr/Abl-negative cells activated p38 MAPK in response to Ara-C (1-β-D-arabinofuranosylcytosine), Bcr/Abl-positive cells were unable to activate p38 MAPK, suggesting that the p38 MAPK pathway is not sensitive to Abl-dependent stimuli in Bcr/Abl-positive cells. Our results demonstrate that the involvement of Bcr/Abl in the p38 MAPK pathway is a key mechanism for explaining resistance to Ara-C, and could provide a clue for new therapeutic approaches based on the use of specific Abl inhibitors.

Download Full-text

TGF-β1 stimulates HO-1 via the p38 mitogen-activated protein kinase in A549 pulmonary epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00151.2002 ◽

2002 ◽

Vol 283 (5) ◽

pp. L1094-L1102 ◽

Cited By ~ 65

Author(s):

Wen Ning ◽

Ruiping Song ◽

Chaojun Li ◽

Edward Park ◽

Amir Mohsenin ◽

...

Keyword(s):

Protein Kinase ◽

Epithelial Cells ◽

Mrna Expression ◽

P38 Mapk ◽

Mapk Pathway ◽

A549 Cells ◽

Mitogen Activated Protein Kinase ◽

P38 Mapk Pathway ◽

Mitogen Activated Protein ◽

Sb 203580

In lung injury and progressive lung diseases, the multifunctional cytokine transforming growth factor-β1 (TGF-β1) modulates inflammatory responses and wound repair. Heme oxygenase-1 (HO-1) is a stress-inducible protein that has been demonstrated to confer cytoprotection against oxidative injury and provide a vital function in maintaining tissue homeostasis. Here we report that TGF-β1 is a potent inducer of HO-1 and examined the signaling pathway by which TGF-β1 regulates HO-1 expression in human lung epithelial cells (A549). TGF-β1(1–5 ng/ml) treatment resulted in a marked time-dependent induction of HO-1 mRNA in A549 cells, followed by corresponding increases in HO-1 protein and HO enzymatic activity. Actinomycin D and cycloheximide inhibited TGF-β1-responsive HO-1 mRNA expression, indicating a requirement for transcription and de novo protein synthesis. Furthermore, TGF-β1 rapidly activated the p38 mitogen-activated protein kinase (p38 MAPK) pathway in A549 cells. A chemical inhibitor of p38 MAPK (SB-203580) abolished TGF-β1-inducible HO-1 mRNA expression. Both SB-203580 and expression of a dominant-negative mutant of p38 MAPK inhibited TGF-β1-induced ho-1 gene activation, as assayed by luciferase activity of an ho-1enhancer/luciferase fusion construct (pMHO1luc-33+SX2). These studies demonstrate the critical intermediacy of the p38 MAPK pathway in the regulation of HO-1 expression by TGF-β1.

Download Full-text

Resveratrol protects H9c2 embryonic rat heart derived cells from oxidative stress by inducing autophagy: role of p38 mitogen-activated protein kinase

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y2012-051 ◽

2012 ◽

Vol 90 (5) ◽

pp. 655-662 ◽

Cited By ~ 38

Author(s):

Xiao Cui Lv ◽

Hai Yan Zhou

Keyword(s):

Oxidative Stress ◽

Protein Kinase ◽

Cell Survival ◽

P38 Mapk ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Protective Effects ◽

H9c2 Cells ◽

P38 Mapk Pathway ◽

Mitogen Activated Protein

Recently, many studies have attempted to illustrate the mechanism of autophagy in protection against oxidative stress to the heart induced by H2O2. However, whether resveratrol-induced autophagy involves the p38 mitogen-activated protein kinase (MAPK) pathway is still unknown. This study aimed to investigate whether treating H9c2 cells with resveratrol increases autophagy and attenuates the cell death and apoptosis induced by oxidative stress via the p38 MAPK pathway. Resveratrol with or without SB202190, an inhibitor of the p38 MAPK pathway, was added 30 min before H2O2. After H2O2 treatment, the cells were incubated under 5% CO2 at 37 °C for 24 h to assess cell survival and death or incubated for 20 min for Western blot and transmission electron microscopy. Flow cytometry was used to detect apoptosis after 6 h of H2O2 treatment. Resveratrol at 20 µmol/L protected H9c2 cells treated with 100 µmol/L H2O2 from oxidative damage. It increased cell survival and markedly decrease lactate dehydrogenase release. In addition, resveratrol increased autophagy and decreased H2O2-induced apoptosis. Furthermore, the protective effects of resveratrol were inhibited by 10 µmol/L SB202190. Thus, resveratrol protected H2O2-treated H9c2 cells by upregulating autophagy via the p38 MAPK pathway.

Download Full-text

The SEK-1 p38 MAP kinase pathway modulates Gq signaling in C. elegans

10.1101/093252 ◽

2016 ◽

Author(s):

Jill M. Hoyt ◽

Samuel K. Wilson ◽

Madhuri Kasa ◽

Jeremy S. Rise ◽

Irini Topalidou ◽

...

Keyword(s):

P38 Mapk ◽

Mapk Pathway ◽

P38 Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Positive Role ◽

C Elegans ◽

Downstream Target ◽

P38 Mapk Pathway ◽

Mitogen Activated Protein ◽

Mature Neurons

AbstractGq is a heterotrimeric G protein that is widely expressed in neurons and regulates neuronal activity. To identify pathways regulating neuronal Gq signaling we performed a forward genetic screen in Caenorhabditis elegans for suppressors of activated Gq. One of the suppressors is an allele of sek-1, which encodes a mitogen-activated protein kinase kinase (MAPKK) in the p38 MAPK pathway. Here we show that sek-1 mutants have a slow locomotion rate and that sek-1 acts in acetylcholine neurons to modulate both locomotion rate and Gq signaling. Furthermore, we find that sek-1 acts in mature neurons to modulate locomotion. Using genetic and behavioral approaches we demonstrate that other components of the p38 MAPK pathway also play a positive role in modulating locomotion and Gq signaling. Finally, we find that mutants in the SEK-1 p38 MAPK pathway partially suppress an activated mutant of the sodium leak channel NCA-1/NALCN, a downstream target of Gq signaling. Our results suggest that the SEK-1 p38 pathway may modulate the output of Gq signaling through NCA-1.

Download Full-text

Thymocyte development past the CD4+CD8+stage requires an active p38 mitogen-activated protein kinase

Blood ◽

10.1182/blood.v95.4.1356.004k23_1356_1361 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1356-1361 ◽

Cited By ~ 10

Author(s):

Edgar Fernández

Keyword(s):

T Cell ◽

Protein Kinase ◽

Cell Line ◽

P38 Mapk ◽

Mapk Pathway ◽

Critical Role ◽

Mitogen Activated Protein Kinase ◽

Cell Functions ◽

Mapk Activity ◽

Mitogen Activated Protein

Activation of the p38 mitogen-activated protein kinase (MAPK) pathway is important for some T-cell functions, but its role in intrathymic development is unclear. To investigate the function of p38 MAPK during the late stages of thymocyte differentiation, pharmacologic and genetic manipulations were used to inhibit p38 MAPK activity in developing thymocytes. Ligation of the T-cell antigen receptor (TCR) on either thymocytes or a thymocyte cell line resulted in p38 MAPK activation. Selective pharmacologic inhibition of p38 MAPK activity with the pyridinyl imidazole drug SB203580 severely impaired the development of mature CD4+ and CD8+ single positive (SP) thymocytes from their CD4+CD8+ double positive (DP) precursors in fetal thymic organ culture (FTOC). Further, pharmacologic or genetic suppression of p38 MAPK activity, the latter achieved by overexpressing a catalytically inactive p38 MAPK, resulted in a blockade of the DP-to-SP transition of a thymocyte cell line in a novel in vitro differentiation assay. Taken together, these data constitute the first demonstration that p38 MAPK plays a critical role in the DP-to-SP differentiation of thymocytes during late intrathymic development.

Download Full-text

Cholesterol is the major component of native lipoproteins activating the p38 mitogen-activated protein kinases

Biological Chemistry ◽

10.1515/bc.2005.106 ◽

2005 ◽

Vol 386 (9) ◽

pp. 909-918 ◽

Cited By ~ 10

Author(s):

Iveta Dobreva ◽

Olaf Zschörnig ◽

Gérard Waeber ◽

Richard W. James ◽

Christian Widmann

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Mapk Pathway ◽

Cholesterol Content ◽

Mitogen Activated Protein Kinase ◽

High Density Lipoproteins ◽

Ldl Particles ◽

P38 Mapk Pathway ◽

Mitogen Activated Protein ◽

P38 Mapks

Abstract Elevated low-density lipoprotein (LDL) levels induce activation of the p38 mitogen-activated protein kinase (MAPK), a stress-activated protein kinase potentially participating in the development of atherosclerosis. The nature of the lipoprotein components inducing p38 MAPK activation has remained unclear however. We show here that both LDLs and high-density lipoproteins (HDLs) have the ability to stimulate the p38 MAPKs with potencies that correlate with their cholesterol content. Cholesterol solubilized in methyl-β-cyclodextrin was sufficient to activate the p38 MAPK pathway. Liposomes made of phosphatidylcholine (PC) or sphingomyelin, the two main phospholipids found in lipoproteins, were unable to stimulate the p38 MAPKs. In contrast, PC liposomes loaded with cholesterol potently activated this pathway. Reducing the cholesterol content of LDL particles lowered their ability to activate the p38 MAPKs. Cell lines representative of the three main cell types found in blood vessels (endothelial cells, smooth muscle cells and fibroblasts) all activated their p38 MAPK pathway in response to LDLs or cholesterol-loaded PC liposomes. These results indicate that elevated cholesterol content in lipoproteins, as seen in hypercholesterolemia, favors the activation of the stress-activated p38 MAPK pathway in cells from the vessel wall, an event that might contribute to the development of atherosclerosis.

Download Full-text

MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00010.2007 ◽

2007 ◽

Vol 293 (5) ◽

pp. F1556-F1563 ◽

Cited By ~ 44

Author(s):

Frank Y. Ma ◽

Greg H. Tesch ◽

Richard A. Flavell ◽

Roger J. Davis ◽

David J. Nikolic-Paterson

Keyword(s):

Inflammatory Response ◽

P38 Mapk ◽

Renal Injury ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Mrna Levels ◽

Direct Role ◽

Mitogen Activated Protein ◽

Early Inflammatory Response ◽

Induced Apoptosis

Activation of the p38 mitogen-activated protein kinase (MAPK) pathway induces inflammation, apoptosis, and fibrosis. However, little is known of the contribution of the upstream kinases, MMK3 and MKK6, to activation of the p38 kinase in the kidney and consequent renal injury. This study investigated the contribution of MKK3 to p38 MAPK activation and renal injury in the obstructed kidney. Groups of eight wild-type (WT) or Mkk3−/− mice underwent unilateral ureteric obstruction (UUO) and were killed 3 or 7 days later. Western blotting showed a marked increase in phospho-p38 (p-p38) MAPK in UUO WT kidney. The same trend of increased p-p38 MAPK was seen in the UUO Mkk3−/− kidney, although the actual level of p-p38 MAPK was significantly reduced compared with WT, and this could not be entirely compensated for by the increase in MKK6 expression in the Mkk3−/− kidney. Apoptosis of tubular and interstitial cells in WT UUO mice was reduced by 50% in Mkk3−/− UUO mice. Furthermore, cultured Mkk3−/− tubular epithelial cells showed resistance to H2O2-induced apoptosis, suggesting a direct role for MKK3-p38 signaling in tubular apoptosis. Upregulation of MCP-1 mRNA levels and macrophage infiltration seen on day 3 in WT UUO mice was significantly reduced in Mkk3−/− mice, but this difference was not evident by day 7. The development of renal fibrosis in Mkk3−/− UUO mice was not different from that seen in WT UUO mice. In conclusion, these studies identify discrete roles for MKK3-p38 signaling in renal cell apoptosis and the early inflammatory response in the obstructed kidney.

Download Full-text