Cortical gamma band oscillations (GBO, 30–80 Hz, typically ∼40 Hz) are involved in higher cognitive functions such as feature binding, attention, and working memory. GBO abnormalities are a feature of several neuropsychiatric disorders associated with dysfunction of cortical fast-spiking interneurons containing the calcium-binding protein parvalbumin (PV). GBO vary according to the state of arousal, are modulated by attention, and are correlated with conscious awareness. However, the subcortical cell types underlying the state-dependent control of GBO are not well understood. Here we tested the role of one cell type in the wakefulness-promoting basal forebrain (BF) region, cortically projecting GABAergic neurons containing PV, whose virally transduced fibers we found apposed cortical PV interneurons involved in generating GBO. Optogenetic stimulation of BF PV neurons in mice preferentially increased cortical GBO power by entraining a cortical oscillator with a resonant frequency of ∼40 Hz, as revealed by analysis of both rhythmic and nonrhythmic BF PV stimulation. Selective saporin lesions of BF cholinergic neurons did not alter the enhancement of cortical GBO power induced by BF PV stimulation. Importantly, bilateral optogenetic inhibition of BF PV neurons decreased the power of the 40-Hz auditory steady-state response, a read-out of the ability of the cortex to generate GBO used in clinical studies. Our results are surprising and novel in indicating that this presumptively inhibitory BF PV input controls cortical GBO, likely by synchronizing the activity of cortical PV interneurons. BF PV neurons may represent a previously unidentified therapeutic target to treat disorders involving abnormal GBO, such as schizophrenia.
Nitric oxide (NO) regulates multiple developmental events and stress responses in plants. A major biologically active species of NO is S-nitrosoglutathione (GSNO), which is irreversibly degraded by GSNO reductase (GSNOR). The major physiological effect of NO is protein S-nitrosylation, a redox-based posttranslational modification mechanism by covalently linking an NO molecule to a cysteine thiol. However, little is known about the mechanisms of S-nitrosylation-regulated signaling, partly due to limited S-nitrosylated proteins being identified. In this study, we identified 1,195 endogenously S-nitrosylated peptides in 926 proteins from the Arabidopsis (Arabidopsis thaliana) by a site-specific nitrosoproteomic approach, which, to date, is the largest data set of S-nitrosylated proteins among all organisms. Consensus sequence analysis of these peptides identified several motifs that contain acidic, but not basic, amino acid residues flanking the S-nitrosylated cysteine residues. These S-nitrosylated proteins are involved in a wide range of biological processes and are significantly enriched in chlorophyll metabolism, photosynthesis, carbohydrate metabolism, and stress responses. Consistently, the gsnor1-3 mutant shows the decreased chlorophyll content and altered photosynthetic properties, suggesting that S-nitrosylation is an important regulatory mechanism in these processes. These results have provided valuable resources and new clues to the studies on S-nitrosylation-regulated signaling in plants.
Nitric oxide (NO) and reactive oxygen species (ROS) are two classes of key signaling molecules involved in various developmental processes and stress responses in plants. The burst of NO and ROS triggered by various stimuli activates downstream signaling pathways to cope with abiotic and biotic stresses. Emerging evidence suggests that the interplay of NO and ROS plays a critical role in regulating stress responses. However, the underpinning molecular mechanism remains poorly understood. Here, we show that NO positively regulates the activity of the Arabidopsis (Arabidopsis thaliana) cytosolic ascorbate peroxidase1 (APX1). We found that S-nitrosylation of APX1 at cysteine (Cys)-32 enhances its enzymatic activity of scavenging hydrogen peroxide, leading to the increased resistance to oxidative stress, whereas a substitution mutation at Cys-32 causes the reduction of ascorbate peroxidase activity and abolishes its responsiveness to the NO-enhanced enzymatic activity. Moreover, S-nitrosylation of APX1 at Cys-32 also plays an important role in regulating immune responses. These findings illustrate a unique mechanism by which NO regulates hydrogen peroxide homeostasis in plants, thereby establishing a molecular link between NO and ROS signaling pathways.
Nitric oxide (NO) regulates diverse cellular signaling through S-nitrosylation of specific Cys residues of target proteins. The intracellular level of S-nitrosoglutathione (GSNO), a major bioactive NO species, is regulated by GSNO reductase (GSNOR), a highly conserved master regulator of NO signaling. However, little is known about how the activity of GSNOR is regulated. Here, we show that S-nitrosylation induces selective autophagy of Arabidopsis GSNOR1 during hypoxia responses. S-nitrosylation of GSNOR1 at Cys-10 induces conformational changes, exposing its AUTOPHAGY-RELATED8 (ATG8)-interacting motif (AIM) accessible by autophagy machinery. Upon binding by ATG8, GSNOR1 is recruited into the autophagosome and degraded in an AIM-dependent manner. Physiologically, the S-nitrosylation-induced selective autophagy of GSNOR1 is relevant to hypoxia responses. Our discovery reveals a unique mechanism by which S-nitrosylation mediates selective autophagy of GSNOR1, thereby establishing a molecular link between NO signaling and autophagy.
LESION SIMULATING DISEASE1 (LSD1) is an important negative regulator of programmed cell death (PCD) in Arabidopsis (Arabidopsis thaliana). The loss-of-function mutations in LSD1 cause runaway cell death triggered by reactive oxygen species. LSD1 encodes a novel zinc finger protein with unknown biochemical activities. Here, we report the identification of CATALASE3 (CAT3) as an LSD1-interacting protein by affinity purification and mass spectrometrybased proteomic analysis. The Arabidopsis genome contains three homologous catalase genes (CAT1, CAT2, and CAT3). Yeast two-hybrid and coimmunoprecipitation analyses demonstrated that LSD1 interacted with all three catalases both in vitro and in vivo, and the interaction required the zinc fingers of LSD1. We found that the catalase enzymatic activity was reduced in the lsd1 mutant, indicating that the catalase enzyme activity was partially dependent on LSD1. Consistently, the lsd1 mutant was more sensitive to the catalase inhibitor 3-amino-1,2,4-triazole than the wild type, suggesting that the interaction between LSD1 and catalases is involved in the regulation of the reactive oxygen species generated in the peroxisome. Genetic studies revealed that LSD1 interacted with CATALASE genes to regulate light-dependent runaway cell death and hypersensitive-type cell death. Moreover, the accumulation of salicylic acid was required for PCD regulated by the interaction between LSD1 and catalases. These results suggest that the LSD1-catalase interaction plays an important role in regulating PCD in Arabidopsis.
CSR LEADS TO A DECOUPLING OF SLEEPINESS FROM SLEEP TIME AND SLEEP INTENSITY, SUGGESTING THAT THERE ARE AT LEAST TWO DIFFERENT SLEEP REGULATORY SYSTEMS: one mediating sleepiness (homeostatic) and the other mediating sleep time/intensity (allostatic). The time course of changes observed in adenosine receptor mRNA levels suggests that the basal forebrain and cortical adenosine system might mediate sleepiness rather than sleep time or intensity.
Oncolytic viruses including oncolytic herpes simplex virus (oHSV) have produced provocative therapeutic responses in patients with glioblastoma (GB), the most aggressive brain tumor. Paradoxically, innate immune responses mediated by natural killer (NK) cells and macrophages/microglia appear to limit oHSV efficacy. Therefore, we investigated whether pretreatment with an immunosuppressive cytokine, TGF-β, might reverse these effects and thereby potentiate oHSV efficacy. TGF-β treatment of NK cells rendered them less cytolytic against oHSV-infected GB cells and stem-like cells in vitro. Further, TGF-β treatment of NK cells, macrophages or microglia increased viral titers of oHSV in co-cultures with GB cells. In a syngeneic mouse model of GB, administering TGF-β prior to oHSV injection inhibited intracranial infiltration and activation of NK cells and macrophages. Notably, a single administration of TGF-β prior to oHSV therapy was sufficient to phenocopy NK cell depletion and suppress tumor growth and prolong survival in both orthograft and syngeneic models of GB. Collectively, our findings show how administering a single dose of TGF-β prior to oncolytic virus treatment of GB can transiently inhibit innate immune cells that limit efficacy, thereby improving therapeutic responses and survival outcomes.
Nitric oxide (NO) is an important signaling molecule regulating diverse biological processes in all living organisms. A major physiological function of NO is executed via protein S‐nitrosylation, a redox‐based posttranslational modification by covalently adding a NO molecule to a reactive cysteine thiol of a target protein. S‐nitrosylation is an evolutionarily conserved mechanism modulating multiple aspects of cellular signaling. During the past decade, significant progress has been made in functional characterization of S‐nitrosylated proteins in plants. Emerging evidence indicates that protein S‐nitrosylation is ubiquitously involved in the regulation of plant development and stress responses. Here we review current understanding on the regulatory mechanisms of protein S‐nitrosylation in various biological processes in plants and highlight key challenges in this field.
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