New discovery of natural immune signals against fungal infections
October 23, 2015 Source: Health
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];
The CARD9 protein is a binding protein downstream of the C-type lectin receptor in the innate immune system and is responsible for transmitting signals generated by upstream receptors recognizing specific substances. C-type lectin receptors mainly include dectin-1, dectin-2, etc., which mainly recognize components of fungal or bacterial cell walls. Activation of the C-type lectin receptor mediates intracellular immune signaling, ultimately inducing activation of NF-kB and release of inflammatory factors.
Initially, CARD9 protein was found to be associated with autoimmune diseases such as IBD (immune bowel disease, ankylosing spondylitis, etc.), and severe fungal infections were also observed in patients with mutations in the CARD9 protein-related gene. Subsequent studies have found that CARD9 protein is located downstream of the C-type lectin receptor, with Dectin-1 as an example. When Dectin-1 is activated by its ligand b-glucans, it triggers phosphorylation of dectin-1, which leads to the downstream kinase syk. Phosphorylation and activation, syk can further activate PKCδ, and activated PKCδ phosphorylates threonine at position 231 of CARD9 protein. Activated CARD9 can bind to two other proteins: BCL10, MALT1 to form a ternary complex, thereby activating NF-kB signaling.
So, is there any other role for CARD9? From the perspective of amino acid composition, we know that the CARD9 protein has a CARD domain at the N-terminus, and the nature and function of its C-terminal amino acid sequence are still unclear. In a recent study, the Ramnik J. Xav team from Harvard Medical School discovered the role of the C-terminus of CARD9 protein in the regulation of innate immune regulation. The results are published in the most recent issue of the journal Immunology.
First, the authors searched and collected a variety of natural CARD9 protein mutation types in the population. By comparison, most of these natural mutants were concentrated at the C-terminus of CARD9. A previously known class of CARD9 mutations (S12N) can cause patients to become more susceptible to IBD, and after C-terminal deletion (Δ11), the resistance of patients to IBD is significantly improved regardless of the presence or absence of the above mutations. This result indicates that the C-terminus of CARD9 protein plays an important role in innate immune signaling.
To further investigate how the C-terminal deletion triggers the above protective effects, the authors transferred two different types of CARD9 mutations (S12N, S12NΔ11) into CARD9-/- mouse bone marrow dendritic cells. The release of downstream inflammatory factors was observed by specific stimulation of receptors such as DECTIN. The results showed that in the presence of S12N, specific stimulation can trigger the release of strong inflammatory factors (TNF-a, IL-6), and when transferred to S12N△11, TNF-a, IL under stimulation The release of -6 was significantly inhibited. This result confirms the role of CARD9 C-terminal for immune signaling. In addition, the authors transferred the C-terminal deleted CARD9 mutant into the wild-type human monocyte cell line THP-1 and primary monocytes, and the results showed that this mutant can competitively inhibit the activity of endogenous CARD9. Thereby inhibiting the release of inflammatory factors.
So what role does the C-side of CARD9 play? By affinity chromatography and mass spectrometry, the authors identified a protein TRIM62 that specifically interacts with the C-terminal of CARD9. This finding was verified by subsequent biochemical and microscopic imaging techniques. Next, the authors studied the biological effects of the interaction of the above proteins. The authors tested this because the TRIM62 protein specifically ubiquitinates the target protein. It was found that TRIM62 can catalyze the ubiquitination of the K27 position of the CARD9 protein, but not the ubiquitination of the C-terminal deletion mutation.
Later, the authors wanted to know if the ubiquitination modification they found determined the biological function of CARD 9. By constructing a lysine mutant at position 127 of CARD (mutation of a key site for ubiquitination mediated by TRIM62), it was found that the mutant could not be successfully ubiquitinated. At the same time, it can not mediate the release of inflammatory factors.
Finally, the authors compared the differences in response between wild-type mice and TRIM62-/- mice during Candida albicans infection. The results showed that the immune response of the mutant mice against fungi was severely damaged, and the fungal infection ability was greatly enhanced.
In summary, the authors discovered the special role of CARD9 protein in fungal infection and identified the relevant role of TRAM62.
Visual Urinalysis Reagent Strip
Urine test strips include :
Urobilinogen
Bilirubin
Ketone
Blood
Protein
Nitrite
Leukocyte
Glucose
Specific Gravity
pH
Ascorbic Acid
Microalbumin
Creatinine
Calcium
1) Rapid Results: 30 seconds to 1 minutes
2) High Quality: Superior European-produced color charts provide consistent, dependable readings
3) Flexible: Available in up to 14 parameters
4) Long shelf life: Consistent Quality with 2 Year Shelf Life
[Intended Use]
Reagent Strips for Urinalysis are used for qualitative and semi- quantitative test of urobilinogen, bilirubin, ketone (acetoacetic acid), blood, protein, nitrite, leukocyte, glucose, specific gravity, pH, ascorbic acid, microalbumin, creatinine, calcium in urine.
[Test Method]
Test environment temperature 25℃±5℃
[Intended Use]
Reagent Strips for Urinalysis are used for qualitative and semi- quantitative test of urobilinogen, bilirubin, ketone (acetoacetic acid), blood, protein, nitrite, leukocyte, glucose, specific gravity, pH, ascorbic acid, microalbumin, creatinine, calcium in urine.
[Main Ingredient]
Urobilinogen:0.3%w/w fast blue B; 98.1%w/w buffer; 1.6%w/w nonreactive ingredients.
Bilirubin:0.6%w/w 2.4-Dichloroaniline diazonium salt;57.9%w/w buffer; 41.5%w/w nonreactive ingredients.
Ketone:5.9%w/w sodium nitroprusside;30.1%w/w buffer;64.0% w/w nonreactive ingredients.
Blood:26.%w/w diisopropylbenzene dihydroperoxide; 1.6%w/w tetramethylbenzidine; 35.3%w/w buffer; 37.1%w/w nonreactive ingredients.
Protein:0.2%w/w tetrabromphenol blue;97.1%w/w buffer; 2.7% w/w nonreactive ingredients.
Nitrite:1.4%w/w p-arsanilic acid;0.9%w/w 1,2,3,4-tetrahydrobenzo(h)quinolin- 3-ol; 89.5%w/w buffer; 8.2%w/w nonreactive ingredients.
Leukocytes:4.3%w/w pyrrole amino acid ester;0.5%w/w diazonium salt; 92.4%w/w buffer;2.8%w/w nonreactive ingredients.
Glucose:1.8%w/w glucose oxidase (123U);0.4%w/w peroxidase (horseradish, 203U); 0.3%w/w potassium iodide;71.0%w/w buffer; 26.5%w/w nonreactive ingredients.
Specific Gravity:4.8%w/w bromothymol blue;90.6%w/w methyl vinyl ether and maleic acid copolymer;4.6%w/w sodium hydroxide.
pH:3.6%w/w methyl red;55.1%w/w bromothymol blue; 41.3% w/w nonreactive ingredients.
Ascorbic Acid: 1.0%W/W2,6-dichlorophenol indophenol sodium;40.7%W/W
buffer;58.3% nonreactive ingredients.
Microalbumin:2.4%W/W phenolsulfonphthalein dye;95.6%W/W buffer; 2.0%W/W nonreactive ingredients.
Visual Urinalysis Reagent Strip,Parameter Urine Strips,Urine Test Strip 10 Parameters,Parameter Urine Test Strips
Changchun ZYF science and technology CO.,LTD , https://www.zyf-medical.com