Casein Kinase 2 Mediates HIV- and Opioid-Induced Pathologic Phosphorylation of TAR DNA Binding Protein 43 in the Basal Ganglia.
Ontology highlight
ABSTRACT: Summary statement
HIV/HIV-1 Tat and morphine independently increase pathologic phosphorylation of TAR DNA binding protein 43 in the striatum. HIV- and opioid-induced pathologic phosphorylation of TAR DNA binding protein 43 may involve enhanced CK2 activity and protein levels.
SUBMITTER: Ohene-Nyako M
PROVIDER: S-EPMC9998424 | biostudies-literature | 2023 Jan-Dec
REPOSITORIES: biostudies-literature
Publications
Casein Kinase 2 Mediates HIV- and Opioid-Induced Pathologic Phosphorylation of TAR DNA Binding Protein 43 in the Basal Ganglia.
Ohene-Nyako Michael M Nass Sara R SR Richard Hope T HT Lukande Robert R Nicol Melanie R MR McRae MaryPeace M Knapp Pamela E PE Hauser Kurt F KF
ASN neuro 20230101
<h4>Summary statement</h4>HIV/HIV-1 Tat and morphine independently increase pathologic phosphorylation of TAR DNA binding protein 43 in the striatum. HIV- and opioid-induced pathologic phosphorylation of TAR DNA binding protein 43 may involve enhanced CK2 activity and protein levels. ...[more]
Similar Datasets
Project description:TAR DNA-binding protein (TDP-43) is a highly conserved and essential DNA- and RNA-binding protein that controls gene expression through RNA processing, in particular, regulation of splicing. Intracellular aggregation of TDP-43 is a hallmark of amyotrophic lateral sclerosis and ubiquitin-positive frontotemporal lobar degeneration. This TDP-43 pathology is also present in other types of neurodegeneration including Alzheimer's disease. We report here that TDP-43 is a substrate of MEK, a central kinase in the MAPK/ERK signaling pathway. TDP-43 dual phosphorylation by MEK, at threonine 153 and tyrosine 155 (p-T153/Y155), was dramatically increased by the heat shock response (HSR) in human cells. HSR promotes cell survival under proteotoxic conditions by maintaining protein homeostasis and preventing protein misfolding. MEK is activated by HSR and contributes to the regulation of proteome stability. Phosphorylated TDP-43 was not associated with TDP-43 aggregation, and p-T153/Y155 remained soluble under conditions that promote protein misfolding. We found that active MEK significantly alters TDP-43-regulated splicing and that phosphomimetic substitutions at these two residues reduce binding to GU-rich RNA. Cellular imaging using a phospho-specific p-T153/Y155 antibody showed that phosphorylated TDP-43 was specifically recruited to the nucleoli, suggesting that p-T153/Y155 regulates a previously unappreciated function of TDP-43 in the processing of nucleolar-associated RNA. These findings highlight a new mechanism that regulates TDP-43 function and homeostasis through phosphorylation and, therefore, may contribute to the development of strategies to prevent TDP-43 aggregation and to uncover previously unexplored roles of TDP-43 in cell metabolism.
| S-EPMC5377819 | biostudies-literature
Project description:Myocardial connexin 43 (Cx43) forms gap junctions and hemichannels, and is also present within subsarcolemmal mitochondria. The protein is phosphorylated by several kinases including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and casein kinase 1 (CK1). A reduction in Cx43 content abrogates myocardial infarct size reduction by ischemic preconditioning (IPC). The present study characterizes the contribution of Cx43 phosphorylation towards mitochondrial function, hemichannel activity, and the cardioprotection by IPC in wild-type (WT) mice and in mice in which Cx43-phosphorylation sites targeted by above kinases are mutated to non-phosphorylatable residues (Cx43MAPKmut, Cx43PKCmut, and Cx43CK1mut mice). The amount of Cx43 in the left ventricle and in mitochondria was reduced in all mutant strains compared to WT mice and Cx43 phosphorylation was altered at residues not directly targeted by the mutations. Whereas complex 1 respiration was reduced in all strains, complex 2 respiration was decreased in Cx43CK1mut mice only. In Cx43 epitope-mutated mice, formation of reactive oxygen species and opening of the mitochondrial permeability transition pore were not affected. The hemichannel open probability was reduced in Cx43PKCmut and Cx43CK1mut but not in Cx43MAPKmut cardiomyocytes. Infarct size in isolated saline-perfused hearts after ischemia/reperfusion (45 min/120 min) was comparable between genotypes and was significantly reduced by IPC (3 × 3 min ischemia/5 min reperfusion) in WT, Cx43MAPKmut, and Cx43PKCmut, but not in Cx43CK1mut mice, an effect independent from the amount of Cx43 and the probability of hemichannel opening. Taken together, our study shows that alterations of Cx43 phosphorylation affect specific cellular functions and highlights the importance of Cx43 phosphorylation by CK1 for IPC's cardioprotection.
| S-EPMC7985055 | biostudies-literature
Project description:TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate approximately 35 and approximately 25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.
| S-EPMC6673167 | biostudies-literature
Project description:Although the interplay between endogenous opioids and dopamine (DA) in the basal ganglia (BG) is known to underlie diverse motor functions, few studies exist on their role in modulating speech and vocalization. Vocal impairment is a common symptom of Parkinson's disease (PD), wherein DA depletion affects striosomes rich in μ-opioid receptors (μ-ORs). Symptoms of opioid addiction also include deficiencies in verbal functions and speech. To understand the interplay between the opioid system and BG in vocalization, we used adult male songbirds wherein high levels of μ-ORs are expressed in Area X, a BG region which is part of a circuit similar to the mammalian thalamocortical-basal ganglia loop. Changes in DA, glutamate and GABA levels were analyzed during the infusion of different doses of the μ-OR antagonist naloxone (50 and 100 ng/ml) specifically in Area X. Blocking μ-ORs in Area X with 100 ng/ml naloxone led to increased levels of DA in this region without altering the number of songs directed toward females (FD). Interestingly, this manipulation also led to changes in the spectro-temporal properties of FD songs, suggesting that altered opioid modulation in the thalamocortical-basal ganglia circuit can affect vocalization. Our study suggests that songbirds are excellent model systems to explore how the interplay between μ-ORs and DA modulation in the BG affects speech/vocalization.
| S-EPMC6618663 | biostudies-literature
Project description:The insular cortex (INS) is extensively connected to the central nucleus of the amygdala (CEA), and both regions send convergent projections into the caudal lateral hypothalamus (LHA) encompassing the parasubthalamic nucleus (PSTN). However, the organization of the network between these structures has not been clearly delineated in the literature, although there has been an upsurge in functional studies related to these structures, especially with regard to the cognitive and psychopathological control of feeding. We conducted tract-tracing experiments from the INS and observed a pathway to the PSTN region that runs parallel to the canonical hyperdirect pathway from the isocortex to the subthalamic nucleus (STN) adjacent to the PSTN. In addition, an indirect pathway with a relay in the central amygdala was also observed that is similar in its structure to the classic indirect pathway of the basal ganglia that also targets the STN. C-Fos experiments showed that the PSTN complex reacts to neophobia and sickness induced by lipopolysaccharide or cisplatin. Chemogenetic (designer receptors exclusively activated by designer drugs [DREADD]) inhibition of tachykininergic neurons (Tac1) in the PSTN revealed that this nucleus gates a stop "no-eat" signal to refrain from feeding when the animal is subjected to sickness or exposed to a previously unknown source of food. Therefore, our anatomical findings in rats and mice indicate that the INS-PSTN network is organized in a similar manner as the hyperdirect and indirect basal ganglia circuitry. Functionally, the PSTN is involved in gating feeding behavior, which is conceptually homologous to the motor no-go response of the adjacent STN.
| S-EPMC7354999 | biostudies-literature
Project description:Neprilysin (NEP) is a type II membrane metalloproteinase that cleaves physiologically active peptides at the cell surface thus regulating the local concentration of these peptides available for receptor binding and signal transduction. In addition, the cytoplasmic N-terminal domain of NEP interacts with the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) thereby regulating intracellular signaling via Akt. Thus, NEP serves dual functions in extracellular and intracellular signal transduction. Here, we show that NEP undergoes phosphorylation at serine residue 6 within the N-terminal cytoplasmic domain. In vitro and cell culture experiments demonstrate that Ser 6 is efficiently phosphorylated by protein kinase CK2. The phosphorylation of the cytoplasmic domain of NEP inhibits its interaction with PTEN. Interestingly, expression of a pseudophosphorylated NEP variant (Ser6Asp) abrogates the inhibitory effect of NEP on insulin/insulin-like growth factor-1 (IGF-1) stimulated activation of Akt. Thus, our data demonstrate a regulatory role of CK2 in the interaction of NEP with PTEN and insulin/IGF-1 signaling.
| S-EPMC2948513 | biostudies-literature
Project description:Casein kinase 1δ (CK1δ) controls essential biological processes including circadian rhythms and wingless-related integration site (Wnt) signaling, but how its activity is regulated is not well understood. CK1δ is inhibited by autophosphorylation of its intrinsically disordered C-terminal tail. Two CK1 splice variants, δ1 and δ2, are known to have very different effects on circadian rhythms. These variants differ only in the last 16 residues of the tail, referred to as the extreme C termini (XCT), but with marked changes in potential phosphorylation sites. Here, we test whether the XCT of these variants have different effects in autoinhibition of the kinase. Using NMR and hydrogen/deuterium exchange mass spectrometry, we show that the δ1 XCT is preferentially phosphorylated by the kinase and the δ1 tail makes more extensive interactions across the kinase domain. Mutation of δ1-specific XCT phosphorylation sites increases kinase activity both in vitro and in cells and leads to changes in the circadian period, similar to what is reported in vivo. Mechanistically, loss of the phosphorylation sites in XCT disrupts tail interaction with the kinase domain. δ1 autoinhibition relies on conserved anion-binding sites around the CK1 active site, demonstrating a common mode of product inhibition of CK1δ. These findings demonstrate how a phosphorylation cycle controls the activity of this essential kinase.
| S-EPMC11474029 | biostudies-literature
Project description:Telomeres located at the ends of linear chromosomes play important roles in the maintenance of life. Rap1, a component of the shelterin telomere protein complex, interacts with multiple proteins to perform various functions; further, formation of shelterin requires Rap1 binding to other components such as Taz1 and Poz1, and telomere tethering to the nuclear envelope (NE) involves interactions between Rap1 and Bqt4, a nuclear membrane protein. Although Rap1 is a hub for telomere protein complexes, the regulatory mechanisms of its interactions with partner proteins are not fully understood. Here, we show that Rap1 is phosphorylated by casein kinase 2 (CK2) at multiple sites, which promotes interactions with Bqt4 and Poz1. Among the multiple CK2-mediated phosphorylation sites of Rap1, phosphorylation at Ser496 was found to be crucial for both Rap1-Bqt4 and Rap1-Poz1 interactions. These mechanisms mediate proper telomere tethering to the NE and the formation of the silenced chromatin structure at chromosome ends.
| S-EPMC6648331 | biostudies-literature
Project description:Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by dopamine deficiency. To elucidate network-level changes through the cortico-basal ganglia pathways in PD, we recorded neuronal activity in PD monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We applied electrical stimulation to the motor cortices and examined responses in the internal (GPi) and external (GPe) segments of the globus pallidus, the output and relay nuclei of the basal ganglia, respectively. In the normal state, cortical stimulation induced a triphasic response composed of early excitation, inhibition, and late excitation in the GPi and GPe. In the PD state, cortically evoked inhibition in the GPi mediated by the cortico-striato-GPi "direct" pathway was largely diminished, whereas late excitation in the GPe mediated by the cortico-striato-GPe-subthalamo (STN)-GPe pathway was elongated. l-DOPA treatment ameliorated PD signs, particularly akinesia/bradykinesia, and normalized cortically evoked responses in both the GPi and GPe. STN blockade by muscimol injection ameliorated the motor deficit and unmasked cortically evoked inhibition in the GPi. These results suggest that information flow through the direct pathway responsible for the initiation of movements is largely reduced in PD and fails to release movements, resulting in akinesia/bradykinesia. Restoration of the information flow through the direct pathway recovers execution of voluntary movements.
| S-EPMC8568006 | biostudies-literature
Project description:The tumor suppressive function of PTEN is exerted within 2 different cellular compartments. In the cytosol-membrane, it negatively regulates PI3K-AKT pathway through the de-phosphorylation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), therefore blocking one of the major signaling transduction pathways in tumorigenesis. In the nucleus, PTEN controls genomic stability and cellular proliferation through phosphatase independent mechanisms. Importantly, impairments in PTEN cellular compartmentalization, changes in protein levels and post-transductional modifications affect PTEN tumor suppressive functions. Targeting mechanisms that inactivate PTEN promotes apoptosis induction of cancer cells, without affecting normal cells, with appealing therapeutic implications. Recently, we have shown that BCR-ABL promotes PTEN nuclear exclusion by favoring HAUSP mediated PTEN de-ubiquitination in Chronic Myeloid Leukemia. Here, we show that nuclear exclusion of PTEN is associated with PTEN inactivation in the cytoplasm of CML cells. In particular, BCR-ABL promotes Casein Kinase II-mediated PTEN tail phosphorylation with consequent inhibition of the phosphatase activity toward PIP3. Targeting Casein Kinase II promotes PTEN reactivation with apoptosis induction. We therefore propose a novel BCR-ABL/CKII/PTEN pathway as a potential target to achieve synthetic lethality with tyrosine kinase inhibitors.
| S-EPMC4615112 | biostudies-literature