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Nihon Yakurigaku Zasshi ; 157(1): 4-8, 2022.
Article Ja | MEDLINE | ID: mdl-34980811

Striated muscle L-type calcium channels (LTCC) are localized specifically to the junctional membrane (JM) where the sarcolemma is closely apposed to the sarcoplasmic reticulum. Although this allocation of LTCC is critical for efficient excitation-contraction coupling in striated muscles, its underlying molecular mechanism has not been clarified. Junctophilins (JPs) stabilize the structure of JM by bridging the sarcolemmal and SR membranes. In addition, immunoprecipitation and pull-down assay revealed that the proximal C-terminus of CaV1.1 subunits directly binds to both JP1 and JP2, indicating that JPs might also directly recruit and hold LTCC in JM. Indeed, expression of a JP1 mutant lacking its C-terminus including the transmembrane domain in mouse skeletal muscles exerted a dominant-negative effect on endogenous JPs by impairing LTCC-RyR coupling at triads and reducing contractile force. To investigate a role of cardiac JP2 in a similar strategy, we injected adeno-associated virus vector expressing a C-terminus lacking JP2 mutant (JP2Δ427) driven by a cardiac troponin T promoter into C57BL/6 mice. Echocardiography recorded 4 weeks after the viral injection showed that the fractional shortening in JP2Δ427 group was significantly decreased compared to that of the control group. Calcium transient of isolated ventricular myocytes was significantly decreased by JP2Δ427 expression. Immunocytochemistry showed that JP2Δ427 recruited LTCC to the surface sarcolemma from T-tubules. Taken together, expression of C-terminus lacking JP mutants down-regulated contractile force by impairing ECC of skeletal and cardiac myocytes. Thus, the physical binding between LTCC and JP is essential for contraction of striated muscles.

Calcium Channels, L-Type , Membrane Proteins , Animals , Calcium/metabolism , Calcium Channels, L-Type/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Myocytes, Cardiac
BMC Infect Dis ; 22(1): 47, 2022 Jan 12.
Article En | MEDLINE | ID: mdl-35022007

BACKGROUND: COVID-19, caused by SARS-CoV-2 has become the most threatening issue to all populations around the world. It is, directly and indirectly, affecting all of us and thus, is an emerging topic dealt in global health. To avoid the infection, various studies have been done and are still ongoing. COVID-19 cases are reported all over the globe, and among the millions of cases, genetic similarity may be seen. The genetical common features seen within confirmed cases may help outline the tendency of infection and degree severity of the disease. Here, we reviewed multiple papers on SNPs related to SARS-CoV-2 infection and analyzed their results. METHODS: The PubMed databases were searched for papers discussing SNPs associated with SARS-CoV-2 infection and severity. Clinical studies with human patients and statistically showing the relevance of the SNP with virus infection were included. Quality Assessment of all papers was done with Newcastle Ottawa Scale. RESULTS: In the analysis, 21 full-text literature out of 2956 screened titles and abstracts, including 63,496 cases, were included. All were human-based clinical studies, some based on certain regions gathered patient data and some based on big databases obtained online. ACE2, TMPRSS2, and IFITM3 are the genes mentioned most frequently that are related to SARS-CoV-2 infection. 20 out of 21 studies mentioned one or more of those genes. The relevant genes according to SNPs were also analyzed. rs12252-C, rs143936283, rs2285666, rs41303171, and rs35803318 are the SNPs that were mentioned at least twice in two different studies. CONCLUSIONS: We found that ACE2, TMPRSS2, and IFITM3 are the major genes that are involved in SARS-CoV-2 infection. The mentioned SNPs were all related to one or more of the above-mentioned genes. There were discussions on certain SNPs that increased the infection and severity to certain groups more than the others. However, as there is limited follow-up and data due to a shortage of time history of the disease, studies may be limited.

COVID-19 , Population Health , Humans , Membrane Proteins/genetics , Polymorphism, Single Nucleotide , RNA-Binding Proteins , SARS-CoV-2
Microb Cell Fact ; 21(1): 6, 2022 Jan 05.
Article En | MEDLINE | ID: mdl-34986868

BACKGROUND: Campylobacter is an animal and zoonotic pathogen of global importance, and a pressing need exists for effective vaccines, including those that make use of conserved polysaccharide antigens. To this end, we adapted Protein Glycan Coupling Technology (PGCT) to develop a versatile Escherichia coli strain capable of generating multiple glycoconjugate vaccine candidates against Campylobacter jejuni. RESULTS: We generated a glycoengineering E. coli strain containing the conserved C. jejuni heptasaccharide coding region integrated in its chromosome as a model glycan. This methodology confers three advantages: (i) reduction of plasmids and antibiotic markers used for PGCT, (ii) swift generation of many glycan-protein combinations and consequent rapid identification of the most antigenic proteins or peptides, and (iii) increased genetic stability of the polysaccharide coding-region. In this study, by using the model glycan expressing strain, we were able to test proteins from C. jejuni, Pseudomonas aeruginosa (both Gram-negative), and Clostridium perfringens (Gram-positive) as acceptors. Using this pgl integrant E. coli strain, four glycoconjugates were readily generated. Two glycoconjugates, where both protein and glycan are from C. jejuni (double-hit vaccines), and two glycoconjugates, where the glycan antigen is conjugated to a detoxified toxin from a different pathogen (single-hit vaccines). Because the downstream application of Live Attenuated Vaccine Strains (LAVS) against C. jejuni is to be used in poultry, which have a higher body temperature of 42 °C, we investigated the effect of temperature on protein expression and glycosylation in the E. coli pgl integrant strain. CONCLUSIONS: We determined that glycosylation is temperature dependent and that for the combination of heptasaccharide and carriers used in this study, the level of PglB available for glycosylation is a step limiting factor in the glycosylation reaction. We also demonstrated that temperature affects the ability of PglB to glycosylate its substrates in an in vitro glycosylation assay independent of its transcriptional level.

Bacterial Proteins/metabolism , Chromosomes/genetics , Escherichia coli/genetics , Escherichia coli/metabolism , Glycoconjugates/metabolism , Temperature , Bacterial Proteins/genetics , Bacterial Vaccines , Campylobacter jejuni/genetics , Campylobacter jejuni/immunology , Glycosylation , Membrane Proteins/genetics , Metabolic Engineering/methods , Polysaccharides, Bacterial/genetics
Yonsei Med J ; 63(1): 42-55, 2022 Jan.
Article En | MEDLINE | ID: mdl-34913283

PURPOSE: Agonists of the stimulator of interferon genes (STING) play a key role in activating the STING pathway by promoting the production of cytokines. In this study, we investigated the antitumor effects and activation of the systemic immune response of treatment with DMXAA (5,6-dimethylxanthenone-4-acetic acid), a STING agonist, in EML4-ALK lung cancer and CT26 colon cancer. MATERIALS AND METHODS: The abscopal effects of DMXAA in the treatment of metastatic skin nodules were assessed. EML4-ALK lung cancer and CT26 colon cancer models were used to evaluate these effects after DMXAA treatment. To evaluate the expression of macrophages and T cells, we sacrificed the tumor-bearing mice after DMXAA treatment and obtained the formalin-fixed paraffin-embedded (FFPE) tissue and tumor cells. Immunohistochemistry and flow cytometry were performed to analyze the expression of each FFPE and tumor cell. RESULTS: We observed that highly infiltrating immune cells downstream of the STING pathway had increased levels of chemokines after DMXAA treatment. In addition, the levels of CD80 and CD86 in antigen-presenting cells were significantly increased after STING activation. Furthermore, innate immune activation altered the systemic T cell-mediated immune responses, induced proliferation of macrophages, inhibited tumor growth, and increased numbers of cytotoxic memory T cells. Tumor-specific lymphocytes also increased in number after treatment with DMXAA. CONCLUSION: The abscopal effect of DMXAA treatment on the skin strongly reduced the spread of EML4-ALK lung cancer and CT26 colon cancer through the STING pathway and induced the presentation of antigens.

Skin Neoplasms , Animals , Immunotherapy , Macrophages , Membrane Proteins/genetics , Mice
FASEB J ; 36(1): e22110, 2022 01.
Article En | MEDLINE | ID: mdl-34918393

Dengue virus (DENV) is a cause of vascular endothelial dysfunction and vascular leakage, which are characterized as hallmarks of dengue hemorrhagic fever or dengue shock syndrome, which become a severe global health emergency with substantial morbidity and mortality. Currently, there are still no promising therapeutics to alleviate the dengue-associated vascular hemorrhage in a clinical setting. In the present study, we first observed that heme oxygenase-1 (HO-1) expression level was highly suppressed in severe DENV-infected patients. In contrast, the overexpression of HO-1 could attenuate DENV-induced pathogenesis, including plasma leakage and thrombocytopenia, in an AG129 mouse model. Our data indicate that overexpression of HO-1 or its metabolite biliverdin can maintain endothelial integrity upon DENV infection in vitro and in vivo. We further characterized the positive regulatory effect of HO-1 on the endothelial adhesion factor vascular endothelial-cadherin to decrease DENV-induced endothelial hyperpermeability. Subsequently, we confirmed that two medicinal plant-derived compounds, andrographolide, and celastrol, widely used as a nutritional or medicinal supplement are useful to attenuate DENV-induced plasma leakage through induction of the HO-1 expression in DENV-infected AG129 mice. In conclusion, our findings reveal that induction of the HO-1 signal pathway is a promising option for the treatment of DENV-induced vascular pathologies.

Capillary Permeability , Dengue Virus/metabolism , Endothelium, Vascular/enzymology , Heme Oxygenase-1/metabolism , Membrane Proteins/metabolism , Severe Dengue/enzymology , Animals , Cell Line , Dengue Virus/genetics , Disease Models, Animal , Heme Oxygenase-1/genetics , Humans , Membrane Proteins/genetics , Mice , Mice, Mutant Strains , Severe Dengue/genetics
Int J Mol Med ; 49(2)2022 02.
Article En | MEDLINE | ID: mdl-34935057

The pathophysiology of coronavirus disease 2019 (COVID­19) is mainly dependent on the underlying mechanisms that mediate the entry of severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) into the host cells of the various human tissues/organs. Recent studies have indicated a higher order of complexity of the mechanisms of infectivity, given that there is a wide­repertoire of possible cell entry mediators that appear to co­localise in a cell­ and tissue­specific manner. The present study provides an overview of the 'canonical' SARS­CoV­2 mediators, namely angiotensin converting enzyme 2, transmembrane protease serine 2 and 4, and neuropilin­1, expanding on the involvement of novel candidates, including glucose­regulated protein 78, basigin, kidney injury molecule­1, metabotropic glutamate receptor subtype 2, ADAM metallopeptidase domain 17 (also termed tumour necrosis factor­α convertase) and Toll­like receptor 4. Furthermore, emerging data indicate that changes in microRNA (miRNA/miR) expression levels in patients with COVID­19 are suggestive of further complexity in the regulation of these viral mediators. An in silico analysis revealed 160 candidate miRNAs with potential strong binding capacity in the aforementioned genes. Future studies should concentrate on elucidating the association between the cellular tropism of the SARS­CoV­2 cell entry mediators and the mechanisms through which they might affect the clinical outcome. Finally, the clinical utility as a biomarker or therapeutic target of miRNAs in the context of COVID­19 warrants further investigation.

COVID-19/metabolism , MicroRNAs/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/virology , /metabolism , Gene Expression Regulation , Host-Pathogen Interactions , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , MicroRNAs/genetics , Neuropilin-1/genetics , Neuropilin-1/metabolism , Receptors, Virus/genetics , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Viral Tropism
J Cell Sci ; 135(5)2022 03 01.
Article En | MEDLINE | ID: mdl-34028531

Lipid droplets (LDs) are globular subcellular structures that store neutral lipids. LDs are closely associated with the endoplasmic reticulum (ER) and are limited by a phospholipid monolayer harboring a specific set of proteins. Most of these proteins associate with LDs through either an amphipathic helix or a membrane-embedded hairpin motif. Here, we address the question of whether integral membrane proteins can localize to the surface of LDs. To test this, we fused perilipin 3 (PLIN3), a mammalian LD-targeted protein, to ER-resident proteins. The resulting fusion proteins localized to the periphery of LDs in both yeast and mammalian cells. This peripheral LD localization of the fusion proteins, however, was due to a redistribution of the ER around LDs, as revealed by bimolecular fluorescence complementation between ER- and LD-localized partners. A LD-tethering function of PLIN3-containing membrane proteins was confirmed by fusing PLIN3 to the cytoplasmic domain of an outer mitochondrial membrane protein, OM14. Expression of OM14-PLIN3 induced a close apposition between LDs and mitochondria. These data indicate that the ER-LD junction constitutes a barrier for ER-resident integral membrane proteins.

Lipid Droplets , Membrane Proteins , Animals , Endoplasmic Reticulum/genetics , Membrane Proteins/genetics , Phospholipids , Saccharomyces cerevisiae
J Cell Sci ; 135(5)2022 03 01.
Article En | MEDLINE | ID: mdl-34156466

Store-operated Ca2+ entry is a central component of intracellular Ca2+ signaling pathways. The Ca2+ release-activated channel (CRAC) mediates store-operated Ca2+ entry in many different cell types. The CRAC channel is composed of the plasma membrane (PM)-localized Orai1 channel and endoplasmic reticulum (ER)-localized STIM1 Ca2+ sensor. Upon ER Ca2+ store depletion, Orai1 and STIM1 form complexes at ER-PM junctions, leading to the formation of activated CRAC channels. Although the importance of CRAC channels is well described, the underlying mechanisms that regulate the recruitment of Orai1 to ER-PM junctions are not fully understood. Here, we describe the rapid and transient S-acylation of Orai1. Using biochemical approaches, we show that Orai1 is rapidly S-acylated at cysteine 143 upon ER Ca2+ store depletion. Importantly, S-acylation of cysteine 143 is required for Orai1-mediated Ca2+ entry and recruitment to STIM1 puncta. We conclude that store depletion-induced S-acylation of Orai1 is necessary for recruitment to ER-PM junctions, subsequent binding to STIM1 and channel activation.

Calcium Channels , Calcium , Acylation , Calcium/metabolism , Calcium Channels/genetics , Calcium Channels/metabolism , Calcium Signaling , Cell Membrane/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , ORAI1 Protein/genetics , ORAI1 Protein/metabolism , Stromal Interaction Molecule 1/genetics , Stromal Interaction Molecule 1/metabolism
Oncol Rep ; 47(2)2022 02.
Article En | MEDLINE | ID: mdl-34859261

Oral squamous cell carcinoma (OSCC) is one of the most common types of head and neck squamous cell carcinoma (HNSCC) with a poor survival rate. In the present study, the involvement of tectonic 1 (TCTN1) in OSCC was explored. The relevance between TCTN1 and HNSCC clinicopathological features was first analyzed and it was revealed that TCTN1 was associated with the tumor clinical stage and grade. In in vitro experiments, it was demonstrated that the proliferative, migratory and invasive capacity of OSCC CAL27 cells and SCC15 cells was significantly suppressed due to TCTN1 knockdown. Additionally, the core promoter of TCTN1 was confirmed and transcription factor AP­2 alpha (TFAP2A) was suggested as a regulator of TCTN1 mRNA expression. On the whole, the present study elucidated the direct association between TCTN1 and OSCC for the first time, to the best of our knowledge, and the TFAP2A/TCTN1 axis was suggested as a potential novel therapeutic target for OSCC.

Gene Expression Regulation, Neoplastic , Membrane Proteins/genetics , Mouth Neoplasms/genetics , Squamous Cell Carcinoma of Head and Neck/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Gene Knockdown Techniques , Humans , Mouth Neoplasms/pathology , Neoplasm Grading , Squamous Cell Carcinoma of Head and Neck/pathology
Gene ; 808: 146000, 2022 Jan 15.
Article En | MEDLINE | ID: mdl-34626719

Hearing loss is a common disease, of which genetic factors are the main cause. The incidence of mild or moderate postlingual deafness in children is not high, and the impact on life and learning is not as severe as that of prelingual deafness. This leads to insufficient attention to the disorder in the clinic. To date, only a few disease-causing genes have been reported. This report describe a case of novel heterozygous mutations in OTOGL that causes nonsyndromic mild sensorineural hearing loss. Basic information, imaging examinations, audiological examination, and vestibular function tests of the proband were collected. Blood samples of the proband's family were collected and analyzed by whole exome sequencing and Sanger sequencing. A pedigree diagram was drawn and the genetic patterns were analyzed. The proband is a 16-year-old female student with mild sensorineural hearing loss. High-resolution CT of the inner ear and vestibular function tests showed no abnormalities. The age of onset was approximately 4 years old. Except for hearing loss, no lesions were seen in other organs. The parents of the proband were not close relatives and had normal hearing. Two novel heterozygous mutations were found in the OTOGL gene. The c.5038del (p.D1680Ifs*6) variant was inherited from the father, and the c.2770C > T (p.R924X) variant from the mother. They enriched the mutation spectrum of OTOGL, which provides the basis for gene function research and genetic consultation.

Hearing Loss, Sensorineural/genetics , Membrane Proteins/genetics , Adolescent , Adult , China , Family , Female , Genotype , Heterozygote , Humans , Male , Membrane Proteins/metabolism , Mutation , Pedigree , Phenotype , Whole Exome Sequencing
Gene ; 807: 145949, 2022 Jan 10.
Article En | MEDLINE | ID: mdl-34481004

Growth traits is a critical economic trait for animal husbandry. In this study, the SNPs of CTNNA3 and CAP2 genes were investigated to check whether they are associated with growth traits (body weight, body height, body length and chest circumference) in Hu sheep. The result of the association analysis indicated that the mutation in CTNNA3 (g.2018018 A > G) were associated significantly with body weight, body height, body length and chest circumference (P < 0.05), the mutation in CAP2 (g.8588 T > C) were associated significantly with body height at 140, 160, 180 days (P < 0.05), AA and CC of CTNNA3 and CAP2 were the dominant genotypes associated with growth traits in Hu sheep. Moreover, combined effect analyses indicated that the growth traits with combined genotypes AACTNNA3-CCCAP2 and AACTNNA3-CTCAP2 were higher than those with genotype GGCTNNA3-CTCAP2. RT-qPCR indicated that CTNNA3 expression levels were significantly higher in liver and lung than in other nine tissues (P < 0.05), CAP2 expression levels were significantly higher in bone, heart, liver, lung and duodenum than in other six tissues (P < 0.05). In conclusion, CTNNA3 and CAP2 polymorphisms could be used as genetic markers for improving growth traits in Hu sheep husbandry.

Adaptor Proteins, Signal Transducing/genetics , Body Weight/genetics , Sheep/growth & development , Animals , China , Genetic Markers/genetics , Genotype , Haplotypes/genetics , Humans , Linkage Disequilibrium , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Phenotype , Polymorphism, Single Nucleotide/genetics , Sheep/genetics , alpha Catenin/genetics , alpha Catenin/metabolism
Biochim Biophys Acta Biomembr ; 1864(1): 183774, 2022 02 01.
Article En | MEDLINE | ID: mdl-34534531

Methods for efficient cyclodextrin-induced lipid exchange have been developed in our lab. These make it possible to almost completely replace the lipids in the outer leaflet of artificial membranes or the plasma membranes of living cells with exogenous lipids. Lipid replacement/substitution allows detailed studies of how lipid composition and asymmetry influence the structure and function of membrane domains and membrane proteins. In this review, we both summarize progress on cyclodextrin exchange in cells, mainly by the use of methyl-alpha cyclodextrin to exchange phospholipids and sphingolipids, and discuss the issues to consider when carrying out lipid exchange experiments upon cells. Issues that impact interpretation of lipid exchange are also discussed. This includes how overly naïve interpretation of how lipid exchange-induced changes in domain formation can impact protein function.

Membrane Lipids/genetics , Membrane Microdomains/genetics , Phospholipids/genetics , alpha-Cyclodextrins/chemistry , Lipid Metabolism/genetics , Membrane Lipids/chemistry , Membrane Microdomains/chemistry , Membrane Proteins/chemistry , Membrane Proteins/genetics , Mutation, Missense/genetics , Phospholipids/chemistry
Biochim Biophys Acta Biomembr ; 1864(1): 183793, 2022 02 01.
Article En | MEDLINE | ID: mdl-34655545

Mycobacterial membrane protein large 3 (Mmpl3) as a trehalose monomycolate lipid transporter contributes to cell wall biosynthesis. Inhibition of Mmpl3 can suppress cell growth and lead to mycobacterial death. SQ109 is a hydrophobic inhibitor of Mmpl3. We have devised a detergent-free strategy to characterize the SQ109/Mmpl3 interaction using the Native Cell Membrane Nanoparticles (NCMN) system, a new method for extracting membrane proteins that better retains native lipids. The homogeneity of the Mmpl3 NCMN particles was confirmed with electron microscopy. The hydrophobic protein-ligand interaction analysis shown for Mmpl3 using the NCMN system may broadly apply to other membrane proteins.

Adamantane/analogs & derivatives , Bacterial Proteins/chemistry , Carrier Proteins/chemistry , Ethylenediamines/chemistry , Membrane Transport Proteins/chemistry , Mycobacterium/chemistry , Adamantane/chemistry , Bacterial Proteins/genetics , Carrier Proteins/genetics , Cell Membrane/chemistry , Lipids/chemistry , Lipids/genetics , Membrane Proteins/chemistry , Membrane Proteins/genetics , Membrane Transport Proteins/genetics , Mycobacterium/genetics , Nanoparticles/chemistry
Biochim Biophys Acta Biomembr ; 1864(1): 183813, 2022 02 01.
Article En | MEDLINE | ID: mdl-34748743

Cellular membranes are fundamental building blocks regulating an extensive repertoire of biological functions. These structures contain lipids and membrane proteins that are known to laterally self-aggregate in the plane of the membrane, forming defined membrane nanoscale domains essential for protein activity. Membrane rafts are described as heterogeneous, dynamic, and short-lived cholesterol- and sphingolipid-enriched membrane nanodomains (10-200 nm) induced by lipid-protein and lipid-lipid interactions. Those membrane nanodomains have been extensively characterized using model membranes and in silico methods. However, despite the development of advanced fluorescence microscopy techniques, undoubted nanoscale visualization by imaging techniques of membrane rafts in the membrane of unperturbed living cells is still uncompleted, increasing the skepticism about their existence. Here, we broadly review recent biochemical and microscopy techniques used to investigate membrane rafts in living cells and we enumerate persistent open questions to answer before unlocking the mystery of membrane rafts in living cells.

Cell Membrane/ultrastructure , Membrane Microdomains/ultrastructure , Membrane Proteins/ultrastructure , Cell Membrane/chemistry , Cell Membrane/genetics , Humans , Ion Transport/genetics , Membrane Microdomains/chemistry , Membrane Microdomains/genetics , Membrane Proteins/chemistry , Membrane Proteins/genetics , Sphingolipids/chemistry , Sphingolipids/genetics
Cancer Lett ; 524: 1-14, 2022 01 01.
Article En | MEDLINE | ID: mdl-34637844

Glucose-related protein 78 (GRP78) is a chaperone protein localized primarily in the endoplasmic reticulum (ER) lumen, where it helps in proper protein folding by targeting misfolded proteins and facilitating protein assembly. In stressed cells, GRP78 is translocated to the cell surface (csGRP78) where it binds to various ligands and triggers different intracellular pathways. Thus, csGRP78 expression is associated with cancer, involved in the maintenance and progression of the disease. Extracellular exposition of csGRP78 leads to the production of autoantibodies as observed in patients with prostate or ovarian cancer, in which the ability to target csGRP78 affects the tumor development. Present on the surface of cancer cells and not normal cells in vivo, csGRP78 represents an interesting target for therapeutic antibody strategies. Here we give an overview of the csGRP78 function in the cell and its role in oncogenesis, thereby providing insight into the clinical value of GRP78 monoclonal antibodies for cancer prognosis and treatment.

/genetics , Ovarian Neoplasms/genetics , Prostatic Neoplasms/genetics , Autoantibodies/immunology , Endoplasmic Reticulum/genetics , Endoplasmic Reticulum/immunology , Female , Humans , Male , Membrane Proteins/genetics , Membrane Proteins/immunology , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Prostatic Neoplasms/immunology , Prostatic Neoplasms/pathology , Signal Transduction
Mol Carcinog ; 61(1): 59-72, 2022 01.
Article En | MEDLINE | ID: mdl-34622496

Enhancer RNAs (eRNAs) are a subclass of long noncoding RNAs (lncRNAs) that have a wide effect in human tumors. However, the systematic analysis of potential functions of eRNAs-related genes (eRGs) in colon cancer (CC) remains unexplored. In this study, a total of 8231 eRGs including 6236 protein-coding genes and 1995 lncRNAs were identified in CC based on the multiple resources. These eRGs showed higher expression level and stability compared to other genes. What's more, the functions of these eRGs were closely related to cancer. Then a prognostic prediction model with 12 eRGs signatures were obtained for colon adenocarcinoma (COAD) patients. ROC curves showed the AUCs were 0.81, 0.77, and 0.78 for 1-, 3-, and 5-year survival prediction, respectively. And the prognostic model also manifested good performance in the validation datasets. Besides, the expression levels of two prognostic signatures, TMEM220 and LRRN2, were verified to be significantly lower in CC tissues than in adjacent noncancerous tissues (p < .05). Finally, the distinct molecular features were characterized between the high- and low-risk group through multiomics analysis including DNA mutation and methylation. Our results show eRGs signatures based prognostic model has high accuracy and may provide innovative biomarkers in COAD.

Biomarkers, Tumor/genetics , Cell Adhesion Molecules, Neuronal/genetics , Colonic Neoplasms/mortality , Membrane Proteins/genetics , RNA, Long Noncoding/genetics , Aged , Aged, 80 and over , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , DNA Methylation , DNA Mutational Analysis , Down-Regulation , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , Sequence Analysis, RNA , Survival Analysis
Article En | MEDLINE | ID: mdl-34517131

Non-shivering thermogenesis (NST) is a heat generating process controlled by the mitochondria of brown adipose tissue (BAT). In the recent decade, 'functionally' acting brown adipocytes in white adipose tissue (WAT) has been identified as well: the so-called process of the 'browning' of WAT. While the importance of uncoupling protein 1 (UCP1)-oriented mitochondrial activation has been intensely studied, the role of peroxisomes during the browning of white adipocytes is poorly understood. Here, we assess the change in peroxisomal membrane proteins, or peroxins (PEXs), during cold stimulation and importantly, the role of PEX13 in the cold-induced remodeling of white adipocytes. PEX13, a protein that originally functions as a docking factor and is involved in protein import into peroxisome matrix, was highly increased during cold-induced recruitment of beige adipocytes within the inguinal WAT of C57BL/6 mice. Moreover, beige-induced 3 T3-L1 adipocytes and stromal vascular fraction (SVF) cells by exposure to the peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone showed a significant increase in mitochondrial thermogenic factors along with peroxisomal proteins including PEX13, and these were confirmed in SVF cells with the beta 3 adrenergic receptor (ß3AR)-selective agonist CL316,243. To verify the relevance of PEX13, we used the RNA silencing method targeting the Pex13 gene and evaluated the subsequent beige development in SVF cells. Interestingly, siPex13 treatment suppressed expression of thermogenic proteins such as UCP1 and PPARγ coactivator 1 alpha (PGC1α). Overall, our data provide evidence supporting the role of peroxisomal proteins, in particular PEX13, during beige remodeling of white adipocytes.

Adipose Tissue, White/metabolism , Membrane Proteins/genetics , PPAR gamma/genetics , Thermogenesis/genetics , Uncoupling Protein 1/genetics , 3T3-L1 Cells , Adipose Tissue, Brown/metabolism , Adrenergic beta-3 Receptor Agonists/pharmacology , Animals , Dioxoles/pharmacology , Mice , Mitochondria/genetics , Mitochondria/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Peroxisomes/genetics , RNA Interference , Receptors, Adrenergic, beta-3/genetics , /metabolism
J Cell Biol ; 221(1)2022 01 03.
Article En | MEDLINE | ID: mdl-34889952

A recent study by Zheng et al. (2021. J. Cell Biol. identifies the ubiquitin-protein ligase (E3) MARCH5 as a dual-organelle localized protein that not only targets to mitochondria but also to peroxisomes in a PEX19-mediated manner. Moreover, the authors demonstrate that the Torin1-dependent induction of pexophagy is executed by the MARCH5-catalyzed ubiquitination of the peroxisomal membrane protein PMP70.

Peroxisomes , Ubiquitin-Protein Ligases , Macroautophagy , Membrane Proteins/genetics , Membrane Proteins/metabolism , Peroxisomes/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitination
J Cell Biol ; 221(1)2022 01 03.
Article En | MEDLINE | ID: mdl-34889953

Cilia harbor diffusion barriers for soluble and membrane proteins within their proximal-most transition zone (TZ) region and employ an intraflagellar transport (IFT) system to form dynamic motile and signaling compartments. In this issue, De-Castro and colleagues (2021. J. Cell Biol. uncover a long-suspected role for the TZ in gating IFT particles.

Cilia , Membrane Proteins , Biological Transport , Cilia/metabolism , Diffusion , Membrane Proteins/genetics , Membrane Proteins/metabolism , Signal Transduction
J Exp Med ; 219(1)2022 01 03.
Article En | MEDLINE | ID: mdl-34901991

Defective DNA clearance in DNase II-/- mice leads to lethal inflammatory diseases that can be rescued by deleting cGAS or STING, but the role of distinct signaling pathways downstream of STING in the disease manifestation is not known. We found that the STING S365A mutation, which abrogates IRF3 binding and type I interferon induction, rescued the embryonic lethality of DNase II-/- mice. However, the STING S365A mutant retains the ability to recruit TBK1 and activate NF-κB, and DNase II-/-STING-S365A mice exhibited severe polyarthritis, which was alleviated by neutralizing antibodies against TNF-α or IL-6 receptor. In contrast, the STING L373A mutation or C-terminal tail truncation, which disrupts TBK1 binding and therefore prevents activation of both IRF3 and NF-κB, completely rescued the phenotypes of DNase II-/- mice. These results demonstrate that TBK1 recruitment to STING mediates autoinflammatory arthritis independently of type I interferons. Inhibiting TBK1 binding to STING may be a therapeutic strategy for certain autoinflammatory diseases instigated by self-DNA.

Arthritis/metabolism , DNA/metabolism , Inflammation/metabolism , Membrane Proteins/metabolism , /metabolism , Animals , Arthritis/genetics , DNA/genetics , Endodeoxyribonucleases/genetics , Endodeoxyribonucleases/metabolism , Inflammation/genetics , Interferon Regulatory Factor-3/metabolism , Interleukin-6/blood , Interleukin-6/genetics , Interleukin-6/metabolism , Membrane Proteins/genetics , Mice, Inbred C57BL , Mice, Knockout , Mutation , NF-kappa B/metabolism , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism