Non-adaptive cognitive emotion regulation mediates the relationship between disease uncertainty and acute stress disorder in patients with ischaemic stroke.

Background: During epidemic outbreaks, hospitalized patients, especially those with cerebrovascular disease, were identified as a vulnerable group suffering from acute stress disorder (ASD) and consequent psychological distress. For stroke patients, not only will they suffer from physical illness, but the uncertainty of illness caused by sudden illness may also cause patients to experience different degrees of ASD. Relevant studies have shown that the impact of ASD on individuals may vary according to age, gender, disease characteristics, individual personality, treatment methods, income level, family support, cognitive psychology and other factors. However, non-adaptive cognitive emotion regulation plays a crucial role in influencing individual psychological states. At present, the risk factors of ASD after stroke and the mechanism between illness uncertainty and cognitive emotion regulation are not fully understood. Therefore, we focus on exploring the predictive effects of general demographic and disease-related characteristics, maladaptive cognitive emotion regulation, and illness uncertainty on ASD after stroke, and make hypotheses. When a disease acts on the body, the patient will have the corresponding cognition of the disease, and ASD will appear at the same time. Then the maladaptive cognitive emotion regulation as an important mediating variable can aggravate the level of acute stress disorder and be verified. Methods: We used a cross-sectional design, which can be used to investigate the distribution of a disease or health condition and its related factors in a specific population at a specific time, so as to describe the distribution of the disease or health condition and its relationship with related factors. A total of 256 hospitalized patients with ischemic stroke were enrolled, including 145 males and 111 females, aged from 26 to 90 years, with a mean age of (64.71 ± 12.20) years. All patients completed and returned a self-report questionnaire that included demographic information, illness uncertainty, cognitive emotion regulation, and ASD. We then compared the differences in general demographic data, illness uncertainty, and maladaptive cognitive emotion regulation in acute stress disorders. Results: The majority of hospitalized stroke patients (67.6%) developed ASD due to the COVID-19 pandemic and were therefore at risk for PTSD. More than one third (39.1%) of stroke survivors also suffered from severe psychological distress. More specifically, younger stroke patients are more likely to experience ASD than older patients. Although higher illness uncertainty scores indicate more severe ASD, adaptive cognitive emotion regulation was a protective factor. Conclusion: Given that individuals with ASD are susceptible to PTSD, it is critical to follow up hospitalized patients with ischemic stroke for screening for PTSD and referral to appropriate psychological services. Maladaptive cognitive emotion regulation can increase the impact of uncertainty on the traumatic experience of stroke patients. Therefore, health care institutions should increase their efforts to provide psychosocial support services to hospitalized patients and make continuous efforts to screen for symptoms of trauma and psychological distress in hospitalized stroke patients.

FGL1 Promotes Tumor Immune Escape in Stomach Adenocarcinoma via the Notch Signaling Pathway.

Immune escape is the major reason for immunotherapy failure in stomach adenocarcinoma (STAD). We tried to reveal the underlying mechanism of FGL1 influencing STAD in this study. Bioinformatics analyses were conducted to analyze the expression of FGL1, the signaling pathways affected by FGL1, and the relation between FGL1 and immune cell infiltration. Quantitative real-time PCR (qRT-PCR), cell counting kit-8 assay, colony formation assay, flow cytometry and Transwell assay were adopted to analyze FGL1 expression, cell viability, cell proliferation, cell apoptosis, and cell invasion, respectively. Enzyme-linked immunosorbent assay, lactate dehydrogenase method, qRT-PCR and Western blot were adopted to reveal proinflammatory cytokine expression, cytotoxicity and mRNA and protein expression of the Notch signaling-related genes, respectively, after co-culture of STAD cells and CD8+T cells. Nude mice experiment was conducted to validate the results obtained above. FGL1 expressed highly in STAD and could activate the Notch signaling pathway, and it was negatively correlated with CD8+T cell infiltration. Cell experiments confirmed that high expression of FGL1 facilitated proliferation and hindered apoptosis of STAD cells. Knockdown of FGL1 could facilitate expression of pro-inflammatory factors and the cytotoxicity of CD8+T cells in co-culture system of STAD and CD8+ T cells. Knockdown of FGL1 could suppress the expression of the Notch signaling pathway-related genes, and the addition of Notch inhibitor proved that FGL1 promoted immune escape via the Notch signaling pathway. This study investigated the influence of FGL1 on STAD immune escape and demonstrated that FGL1 inhibited CD8+ T cell activation by activating the Notch signaling pathway and thus promoted tumor immune escape in STAD, providing a new potential diagnostic marker and therapeutic target for the immunotherapy of STAD patients.

A Case of Critical Japanese Spotted Fever in Zhejiang, China.

Background: Japanese spotted fever (JSF) is a rare disease, caused by Rickettsia japonica; no case has been reported in Zhejiang Province, China. Case Presentation: An elderly woman presented to the hospital with abdominal pain and fever. Her condition rapidly worsened with severe complications, such as multiple organ failure and central nervous system damage. The presence of R. japonica was quickly detected by metagenomic next-generation sequencing. On the basis of combined clinical manifestations and laboratory results, critical JSF was diagnosed and treated with doxycycline. The patient showed good prognosis. Typical symptoms (eschar and rash) were not observed in the early stage, consequently increasing the difficulty of clinical diagnosis. Conclusion: The delay of treatment caused by non-specific symptoms is an important factor affecting the progression of JSF. As an emerging pathogen detection method, mNGS has been successfully applied for disease diagnosis and treatment, and can be an important complement for the diagnosis of this disease.

Developing a Diagnostic Model to Predict the Risk of Asthma Based on Ten Macrophage-Related Gene Signatures.

Objective: Asthma (AS) is a chronic inflammatory disease of the airway, and macrophages contribute to AS remodeling. Our study aims at screening macrophage-related gene signatures to build a risk prediction model and explore its predictive abilities in AS diagnosis. Methods: Three microarray datasets were downloaded from the GEO database. The Limma package was used to screen differentially expressed genes (DEGs) between AS and controls. The ssGSEA algorithm was used to determine immune cell proportions. The Pearson correlation coefficient was computed to select the macrophage-related DEGs. The LASSO and RFE algorithms were implemented to filter the macrophage-related DEG signatures to establish a risk prediction model. Receiver operating characteristic (ROC) curves were used to assess the diagnostic ability of the prediction model. Finally, the qPCR was used to detect the expression of selected differential genes in sputum from healthy people and asthmatic patients. Results: We obtained 1,189 DEGs between AS and controls from the combined datasets. By evaluating immune cell proportions, macrophages showed a significant difference between the two groups, and 439 DEGs were found to be associated with macrophages. These genes were mainly enriched in the gene ontology-biological process of immune and inflammatory responses, as well as in the KEGG pathways of cytokine-cytokine receptor interaction and biosynthesis of antibiotics. Finally, 10 macrophage-related DEG signatures (EARS2, ATP2A2, COLGALT1, GART, WNT5A, AK5, ZBTB16, CCL17, ADORA3, and CXCR4) were screened as an optimized gene set to predict AS diagnosis, and they showed diagnostic abilities with AUCs of 0.968 and 0.875 in ROC curves of combined and validation datasets, respectively. The mRNA expressions of EARS2, ATP2A2, COLGALT1, and GART in the control group were higher than in AS group, while the expressions of WNT5A, AK5, ZBTB16, CCL17, ADORA3, and CXCR4 in the control group were lower than that in the AS group. Conclusion: We proposed a diagnostic model based on 10 macrophage-related genes to predict AS risk.\.

Indole-Based Long-Wavelength Fluorescent Probes for Bioimaging of S-Nitrosylation in Mitochondria.

S-Nitrosylation has been found to play an important role in regulating mitochondrial function. However, probes for detection of protein S-nitrosylation in mitochondria remain unexplored. Herein, a novel 4-(pyridin-4-yl)vinyl-substituted indole was designed, exhibiting a long-wavelength emission and a high fluorescent quantum yield. Functionalization of the 7-position of the indole ring with an arylphosphine ester resulted with probes with efficient mitochondria-targeting ability. Furthermore, the indole-arylphosphine displayed a significant fluorescence enhancement upon exposure to S-nitrosoglutathione (GSNO) at low micromolar concentrations in A431 cells. Taken together, this study provides a new indole-based fluorescent probe with a unique long-wavelength emission for direct detection of S-nitrosylation in mitochondria, which may represent a powerful tool for understanding the critical roles of S-nitrosylation within mitochondria of living organisms.

A CDR-based approach to generate covalent inhibitory antibody for human rhinovirus protease.

Covalent target modulation with small molecules has been emerging as a promising strategy for drug discovery. However, covalent inhibitory antibody remains unexplored due to the lack of efficient strategies to engineer antibody with desired bioactivity. Herein, we developed an intracellular selection method to generate covalent inhibitory antibody against human rhinovirus 14 (HRV14) 3C protease through unnatural amino acid mutagenesis along the heavy chain complementarity-determining region 3 (CDR-H3). A library of antibody mutants was thus constructed and screened in vivo through co-expression with the target protease. Using this screening strategy, six covalent antibodies with proximity-enabled bioactivity were identified, which were shown to covalently target HRV14-3C protease with high inhibitory potency and exquisite selectivity. Compared to structure-based rational design, this library-based screening method provides a simple and efficient way for the discovery and engineering of covalent antibody for enzyme inhibition.

Role of long noncoding RNA taurine-upregulated gene 1 in cancers.

Long non-coding RNAs (lncRNAs) are a group of non-protein coding RNAs with a length of more than 200 bp. The lncRNA taurine up-regulated gene 1 (TUG1) is abnormally expressed in many human malignant cancers, where it acts as a competitive endogenous RNA (ceRNA), regulating gene expression by specifically sponging its corresponding microRNAs. In the present review, we summarised the current understanding of the role of lncRNA TUG1 in cancer cell proliferation, metastasis, angiogenesis, chemotherapeutic drug resistance, radiosensitivity, cell regulation, and cell glycolysis, as well as highlighting its potential application as a clinical biomarker or therapeutic target for malignant cancer. This review provides the basis for new research directions for lncRNA TUG1 in cancer prevention, diagnosis, and treatment.

Suzuki Cross-Coupling Reaction with Genetically Encoded Fluorosulfates for Fluorogenic Protein Labeling.

A palladium-catalyzed cross-coupling reaction with aryl halide functionalities has recently emerged as a valuable tool for protein modification. Herein, a new fluorogenic modification methodology for proteins, with genetically encoded fluorosulfate-l-tyrosine, which exhibits high efficiency and biocompatibility in bacterial cells as well as in aqueous medium, is described. Furthermore, the cross-coupling of 4-cyanophenylboronic acid on green fluorescent protein was shown to possess a unique fluorogenic property, which could open up the possibility of a responsive "off/on" switch with great potential to enable spectroscopic imaging of proteins with minimal background noise. Taken together, a convenient and efficient catalytic system has been developed that may provide broad utilities in protein visualization and live-cell imaging.

The Antimalarial Natural Product Salinipostin A Identifies Essential α/ß Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites.

Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/ß serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets.

[Mechanism of catgut embedding at back-shu points for nonalcoholic steatohepatitis based on IKK/IKB/NF-κB signaling pathway].

OBJECTIVE: To explore the mechanism of catgut embedding at back-shu points on nonalcoholic steatohepatitis (NASH) in rats based on IKK/IKB/NF-κB signaling pathway and downstream inflammatory factors. METHODS: Eighty SPF SD rats were selected, among them 10 rats were selected divided into a normal group (group A), and the remaining 70 rats were fed with high-fat diet to establish NASH model. At the end of 12 weeks, 10 rats were randomly selected to verify whether the model establishment was successful. Then the remaining 60 rats were randomly divided into a model group (group B), a catgut embedding at back-shu points group (group C), a catgut embedding at abdominal points group (group D), an acupuncture at back-shu points group (group E), a sham catgut embedding group (group F) and a western medication group (group G), 10 rats in each group. The rats in the group C were treated with catgut embedding at "Ganshu" (BL 18), "Pishu" (BL 20), "Weishu" (BL 21) and "Shenshu" (BL 23); the rats in the group D were treated with catgut embedding at "Daheng" (SP 15), "Fujie" (SP 14), "Huaroumen" (ST 24) and "Tianshu" (ST 25); the rats in the group E were treated with acupuncture at the same acupoints as the group C; the rats in the group F were treated with catgut embedding at back-shu points but the needle did not enter subcutaneous tissue gamma; the rats in the group G were treated with intragastric administration of vitamin E capsule. All the treatment was given for 4 weeks. The rats in the group A were fed with normal diet until the end of 16 weeks without any intervention. The rats in the group B continued to be fed with high-fat diet until the end of 16 weeks. After the intervention, the liver index was calculated; the liver histomorphology was observed by HE staining; the liver function [alanine aminotransferase (ALT), gamma glutamyl transferase (γ-GGT), alkaline phosphatase (ALP)] and blood lipid [serum total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL)] were measured by serum biochemistry. The serum levels of TNF-α, IL-6 and IL-1ßwere detected by ELISA, and the expressions of IKK-α, NF-κBp65, IL-6, IL-1ß and TNF-α proteins in liver tissue were detected by Western blot. The temperature of the conception vessel and the governor vessel was measured by infrared thermography. RESULTS: Compared with the group A, the obvious steatosis and inflammatory cell infiltration were observed in the group B, and the body weight, liver wet-weight and liver index were all increased (P<0.01). Compared with the group B, the liver tissue morphology in the group C, the group D, the group E and the group G was improved in varying degrees, and the liver index was decreased (P<0.05), which was the most significant in the group C (P<0.05). Compared with the group A, the ALT, γ-GGT, ALP, TG, TC, LDL, TNF-α, IL-6 and IL-1ß were all increased in the group B (P<0.01); compared with the group B, the ALT, γ-GGT, ALP, TG, TC, LDL, TNF-α, IL-6 and IL-1ß in all intervention groups were all decreased in varying degrees (P<0.01, P<0.05), which was the most significant in the group C (P<0.01). Compare with the group A, the expressions of IKK-α, NF-κBp65, TNF-α, IL-6 and IL-1ßproteins in the group B were all increased (P<0.01); compared with the group B, the expressions of IKK-α, NF-κBp65, TNF-α, IL-6 and IL-1ßproteins in all intervention groups were decreased in varying degrees (P<0.05), which was the most significant in the group C (P<0.01). Compared with the group A, the temperature of the conception vessel and governor vessel was decreased in the group B (P<0.01). Compared with the group B, the temperature of the conception vessel and governor vessel was all increased in the group C, the group D and the group E (P<0.01); the temperature of the conception vessel in the group C was similar to that in the group D (P>0.05), while the temperature of the governor vessel in the group C was superior to that in the group D (P<0.05). CONCLUSION: The catgut embedding at back-shu points might inhibit the activation of IKK/IKB/NF-κB signaling pathway to interrupt the inflammatory cascade, and reduce the "second hit" of inflammatory factors on liver, which could slow down NASH progress and prevent and treat NASH.

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones.

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. Recently, we have developed an efficient organocatalytic strategy, which provides facile access to a variety of enantiomerically enriched bispiro[γ-butyrolactone-pyrrolidin-4,4'-pyrazolone] skeletons. In this paper, we demonstrate a detailed protocol for the asymmetric synthesis of drug-like bispirocyclic compounds with two spirocyclic carbon centers via an organocatyltic 1,3-dipolar cycloaddition reaction. Spirocyclization synthons α-imino γ-lactones and alkylidene pyrazolones are prepared first, which are then subjected to a cycloaddition reaction in the presence of a bifunctional squaramide organocatalyst to afford the desired bispirocycles in high yields and excellent stereoselectivities. Chiral high-performance liquid chromatography (HPLC) is carried out to determine the enantiomeric purity of the products, and the d.r. value is examined by proton nuclear magnetic resonance (1H NMR). The absolute configuration of the product is assigned according to an X-ray crystallographic analysis. This synthetic strategy allows scientists to prepare a diversity of bispirocyclic scaffolds in high yields and excellent diastereo- and enantioselectivities.

Inhibition of S-Adenosylhomocysteine Hydrolase Induces Endothelial Dysfunction via Epigenetic Regulation of p66shc-Mediated Oxidative Stress Pathway.

BACKGROUND: Elevated levels of S-adenosylhomocysteine (SAH), the precursor of homocysteine, are positively associated with the risk of cardiovascular disease and with the development and progression of atherosclerosis. However, the role of SAH in endothelial dysfunction is unclear. METHODS: Apolipoprotein E-deficient ( apoE-/-) mice received dietary supplementation with the SAH hydrolase (SAHH) inhibitor adenosine dialdehyde or were intravenously injected with a retrovirus expressing SAHH shRNA. These 2 approaches, along with the heterozygous SAHH gene knockout ( SAHH+/-) mouse model, were used to elevate plasma SAH levels and to examine the role of SAH in aortic endothelial dysfunction. The relationship between plasma SAH levels and endothelial dysfunction was also investigated in human patients with coronary artery disease and healthy control subjects. RESULTS: Plasma SAH levels were increased in SAHH+/- mice and in apoE-/- mice after dietary administration of adenosine dialdehyde or intravenous injection with SAHH shRNA. SAHH+/- mice or apoE-/- mice with SAHH inhibition showed impaired endothelium-dependent vascular relaxation and decreased nitric oxide bioavailability after treatment with acetylcholine; this was completely abolished by the administration of the endothelial nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. Furthermore, SAHH inhibition induced production of reactive oxygen species and p66shc expression in the mouse aorta and human aortic endothelial cells. Antioxidants and p66shc siRNA prevented SAHH inhibition-induced generation of reactive oxygen species and attenuated the impaired endothelial vasomotor responses in high-SAH mice. Moreover, inhibition of SAHH induced hypomethylation in the p66shc gene promoter and inhibited expression of DNA methyltransferase 1. Overexpression of DNA methyltransferase 1, induced by transduction of an adenovirus, was sufficient to abrogate SAHH inhibition-induced upregulation of p66shc expression. Finally, plasma SAH levels were inversely associated with flow-mediated dilation and hypomethylation of the p66shc gene promoter and positively associated with oxidative stress levels in patients with coronary artery disease and healthy control subjects. CONCLUSIONS: Our findings indicate that inhibition of SAHH results in elevated plasma SAH levels and induces endothelial dysfunction via epigenetic upregulation of the p66shc-mediated oxidative stress pathway. Our study provides novel molecular insight into mechanisms of SAH-associated endothelial injury that may contribute to the development of atherosclerosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03345927.

Chemoproteomic Strategy to Quantitatively Monitor Transnitrosation Uncovers Functionally Relevant S-Nitrosation Sites on Cathepsin D and HADH2.

S-Nitrosoglutathione (GSNO) is an endogenous transnitrosation donor involved in S-nitrosation of a variety of cellular proteins, thereby regulating diverse protein functions. Quantitative proteomic methods are necessary to establish which cysteine residues are most sensitive to GSNO-mediated transnitrosation. Here, a competitive cysteine-reactivity profiling strategy was implemented to quantitatively measure the sensitivity of >600 cysteine residues to transnitrosation by GSNO. This platform identified a subset of cysteine residues with a high propensity for GSNO-mediated transnitrosation. Functional characterization of previously unannotated S-nitrosation sites revealed that S-nitrosation of a cysteine residue distal to the 3-hydroxyacyl-CoA dehydrogenase type 2 (HADH2) active site impaired catalytic activity. Similarly, S-nitrosation of a non-catalytic cysteine residue in the lysosomal aspartyl protease cathepsin D (CTSD) inhibited proteolytic activation. Together, these studies revealed two previously uncharacterized cysteine residues that regulate protein function, and established a chemical-proteomic platform with capabilities to determine substrate specificity of other cellular transnitrosation agents.

A clickable glutathione approach for identification of protein glutathionylation in response to glucose metabolism.

Glucose metabolism and mitochondrial function are closely interconnected with cellular redox-homeostasis. Although glucose starvation, which mimics ischemic conditions or insufficient vascularization, is known to perturb redox-homeostasis, global and individual protein glutathionylation in response to glucose metabolism or mitochondrial activity remains largely unknown. In this report, we use our clickable glutathione approach, which forms clickable glutathione (azido-glutathione) by using a mutant of glutathione synthetase (GS M4), for detection and identification of protein glutathionylation in response to glucose starvation. We found that protein glutathionylation is readily induced in HEK293 cells in response to low glucose concentrations when mitochondrial reactive oxygen species (ROS) are elevated in cells, and glucose is the major determinant for inducing reversible glutathionylation. Proteomic and biochemical analysis identified over 1300 proteins, including SMYD2, PP2Cα, and catalase. We further showed that PP2Cα is glutathionylated at C314 in a C-terminal domain, and PP2Cα C314 glutathionylation disrupts the interaction with mGluR3, an important glutamate receptor associated with synaptic plasticity.

[Acupuncture and moxibustion based on meridian differentiation for cervical spondylosis radiculopathy:a randomized controlled trial].

OBJECTIVE: To observe the difference of clinical effects of acupoints selected based on meridian differen-tiation and conventional method for cervical spondylosis radiculopathy(CSR) treated with acupuncture and moxibustion. METHODS: Sixty patients with CSR were randomly divided into an observation group and a control group,30 cases in each one. Ashi points of the injured meridians in the neck,namely six-he points,were selected in the observation group,matched with luo-connecting points of the injured meridians on the same side and the interiorly-exteriorly correlated meridians on the opposite side. Conventional acupuncture was used on Fengchi(GB 20),Jiaji(EX-B 2) of the neck,Tianzhu(BL 10),Jianjing(GB 21),Houxi(SI 3),Hegu(LI 4) and Waiguan(TE 5) on the affected side in the control group. Treatment was given once every other day,three times a week and total 12 times in the two groups. Twenty subscales for CSR and visual analogue scale(VAS) were observed before and after treatment,and total effects were evaluated after treatment. RESULTS: The effective rate of the observation group was 93.3%(28/30),which was better than 66.7%(20/30) of the control group(P<0.05). The scores of 20 subscales and VAS after treatment were all improved compared with those before treatment in the two groups(all P<0.01),with more apparent change in the observation group(both P<0.05). CONCLUSIONS: The effect of acupuncture and moxibustion based on meridian differentiation is obvious,and superior to that of conventional acupoints selection.

Chemical-proteomic strategies to investigate cysteine posttranslational modifications.

The unique combination of nucleophilicity and redox-sensitivity that is characteristic of cysteine residues results in a variety of posttranslational modifications (PTMs), including oxidation, nitrosation, glutathionylation, prenylation, palmitoylation and Michael adducts with lipid-derived electrophiles (LDEs). These PTMs regulate the activity of diverse protein families by modulating the reactivity of cysteine nucleophiles within active sites of enzymes, and governing protein localization between soluble and membrane-bound forms. Many of these modifications are highly labile, sensitive to small changes in the environment, and dynamic, rendering it difficult to detect these modified species within a complex proteome. Several chemical-proteomic platforms have evolved to study these modifications and enable a better understanding of the diversity of proteins that are regulated by cysteine PTMs. These platforms include: (1) chemical probes to selectively tag PTM-modified cysteines; (2) differential labeling platforms that selectively reveal and tag PTM-modified cysteines; (3) lipid, isoprene and LDE derivatives containing bioorthogonal handles; and (4) cysteine-reactivity profiling to identify PTM-induced decreases in cysteine nucleophilicity. Here, we will provide an overview of these existing chemical-proteomic strategies and their effectiveness at identifying PTM-modified cysteine residues within native biological systems.

MsrB1 and MICALs regulate actin assembly and macrophage function via reversible stereoselective methionine oxidation.

Redox control of protein function involves oxidation and reduction of amino acid residues, but the mechanisms and regulators involved are insufficiently understood. Here, we report that in conjunction with Mical proteins, methionine-R-sulfoxide reductase B1 (MsrB1) regulates mammalian actin assembly via stereoselective methionine oxidation and reduction in a reversible, site-specific manner. Two methionine residues in actin are specifically converted to methionine-R-sulfoxide by Mical1 and Mical2 and reduced back to methionine by selenoprotein MsrB1, supporting actin disassembly and assembly, respectively. Macrophages utilize this redox control during cellular activation by stimulating MsrB1 expression and activity as a part of innate immunity. We identified the regulatory role of MsrB1 as a Mical antagonist in orchestrating actin dynamics and macrophage function. More generally, our study shows that proteins can be regulated by reversible site-specific methionine-R-sulfoxidation.