Potential role of cyclophilin A in regulating cytokine secretion

Dawar, Farman Ullah; Xiong, Yang; Khattak, Muhammad Nasir Khan; Li, Jun; Lin, Li; Mei, Jie

doi:10.1189/jlb.3ru0317-090rr

Cited by 73 publications

(55 citation statements)

References 60 publications

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“…13 CD147 is also presented in activated inflammatory cells and participates the regulation of cytokine secretion and leukocytes chemotaxis by binding with cyclophilin A (CyPA). 14,15 CyPA is a proinflammatory cytokine that is up-regulated in response to virus infection. 16 Our previous studies demonstrated that antibody targeting CD147 inhibited CyPA-induced T cell chemotaxis thus attenuating the local inflammation.…”

Section: Introductionmentioning

confidence: 99%

Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial

Bian

Zheng

Ding

et al. 2020

Preprint

140

135

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Background: SARS-CoV-2 is a novel human coronavirus, there is no specific antiviral drugs. It has been proved that host-cell-expressed CD147 could bind spike protein of SARS-CoV-2 and involve in host cell invasion. Antibody against CD147 could block the infection of SARS-CoV-2. We aimed to assess the efficacy and safety of meplazumab, a humanized anti-CD147 antibody, as add-on therapy in patients with COVID-19 pneumonia. Methods: All patients received recommended strategy from Diagnosis and Treatment for 2019 Novel Coronavirus Diseases released by National Health Commission of China. Eligible patients were add-on administered 10 mg meplazumab intravenously at days 1, 2, and 5. Patients hospitalized in the same period were observed as concurrent control. The endpoints include virological clearance rate, case severity, chest radiographic, and laboratory test. This trial was approved by the Ethics Committee of Institution at the Tangdu hospital, and registered with ClinicalTrials.gov, NCT 04275245. Findings:17 patients were enrolled and assigned to meplazumab group between Feb 3, 2020 and Feb 10, 2020. 11 hospitalized patients served as concurrent control. Baseline characteristics were generally balanced across two groups. Compared to control group, meplazumab treatment significantly improved the discharged (p=0.006) and case severity (p=0.021) in critical and severe patients. The time to virus negative in meplazumab group was reduced than that in control group (median 3, 95%CI[1.5-4.5] vs. 13, [6.5-19.5]; p=0.014, HR=0.37, 95%CI[0.155-0.833]). The percentages of patients recovered to the normal lymphocyte count and CRP concentration were also increased remarkably and rapidly in meplazumab group. No adverse effect was found in meplazumab-treated patients. Interpretation:Meplazumab efficiently improved the recovery of patients with SARS-CoV-2 pneumonia with a favorable safety profile. Our results support to carry out a large-scale investigation of meplazumab as a treatment for COVID-19 pneumonia. Funding:National Science and Technology Major Project.

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Section: Introductionmentioning

confidence: 99%

Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial

Bian

Zheng

Ding

et al. 2020

Preprint

140

135

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“…CypA is a member of the cyclophilin family proteins that have peptidyl‐prolyl isomerase activity and are thought to play an important role in protein folding . Meanwhile, CypA is a pro‐inflammatory regulator that could regulate various immunity reaction with pathogen invasion . To verify the interaction between PknG and CypA, we used BLI, finding that PknG indeed strongly binds to CypA (Figure A).…”

Section: Resultsmentioning

confidence: 99%

“…[33] Meanwhile, CypA is a pro-inflammatory regulator that could regulate various immunity reaction with pathogen invasion. [34] To verify the interaction between PknG and CypA, we used BLI, finding that PknG indeed strongly binds to CypA (Figure 4A). We also verified this interaction in vivo by co-IP, PknG was overexpressed in 293T cells.…”

Section: Cypa Is a Substrate Of Pkngmentioning

confidence: 99%

Global Profiling of PknG Interactions Using a Human Proteome Microarray Reveals Novel Connections with CypA

Liu

Zhang

et al. 2018

Proteomics

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Mycobacterium tuberculosis (Mtb) serine/threonine kinase PknG plays an important role in the Mtb–host interaction by facilitating the survival of Mtb in macrophages. However, the human proteins with which the PknG interacts, and the underlying molecular mechanisms are still largely unknown. In this study, a HuProt array is been applied to globally identify the host proteins to which PknG binds. In this way, 125 interactors are discovered, including a cyclophilin protein, CypA. This interaction between PknG and CypA is validated both in vitro and in vivo, and functional studies show that PknG significantly reduces the protein levels of CypA through phosphorylation, which consequently inhibit the inflammatory response through downregulation of NF‐κB and ERK1/2 pathways. Phenotypically, overexpression of PknG reduces cytokine levels and promotes the survival of Mycobacterium smegmatis (Msm) in macrophages. Overall, it is expected that the PknG interactors identified in this study will serve as a useful resource for further systematic studies of the roles that PknG plays in the Mtb‐host interactions.

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“…Cyclophilin A (CyA), an 18 kDa peptidylprolyl cis-trans isomerase, is a ubiquitous and multifunctional protein. In addition to its role as a host-cell receptor for cyclosporine A, CyA has diverse functions in inflammatory conditions and diseases [15,16]. The 52-kDa FK506-binding protein (FKBP52) an immunophilin belonging to the FKBP family, is a known co-chaperone of the heat shock protein 90 (HSP90) and thus may play a role in the intracellular trafficking of hetero-oligomeric forms of the steroid hormone receptors [17,18].…”

Section: Introductionmentioning

confidence: 99%

The dengue virus non-structural protein 1 (NS1) is secreted from mosquito cells in association with the intracellular cholesterol transporter chaperone caveolin complex

Ramirez

Ludert

2018

Preprint

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11 12 Keywords: 13 dengue virus; zika virus; yellow fever virus; flavivirus; NS1; caveolin-1; chaperone caveolin 14 complex; viral protein trafficking; unconventional secretion; mosquito cells 15 16 17 ABSTRACT 18 Dengue virus (DENV) is a mosquito-borne virus of the family Flaviviridae. The RNA viral genome 19 encodes for a polyprotein that is co-translationally processed into three structural proteins and . CC-BY 4.0 International license is made available under aThe copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/370932 doi: bioRxiv preprint 2 20 seven non-structural proteins. The non-structural protein 1 (NS1) is a multifunctional viral protein 21 actively secreted in vertebrate and mosquito cells during DENV infection. In mosquito cells, NS1 22 is secreted in a caveolin-1 (CAV-1) dependent manner by an unconventional pathway. The 23 caveolin chaperone complex (CCC) is a cytoplasmic complex formed by caveolin-1 and the 24 chaperones FKBP52, Cy40 and CyA which is responsible for cholesterol traffic inside the cell. 25 In this work, we demonstrate that in infected mosquito cells, DENV NS1 is secreted by an early 26 and unconventional route that bypasses the Golgi apparatus in close association with the CCC.27 Treatment of mosquito cells with classic secretion inhibitors such as brefeldin A, golgicide A and 28 Fli-06 showed no effect on NS1 secretion, but significant reductions in recombinant luciferase 29 secretion and virion release. Silencing the expression of CAV1, FKBP52 with siRNAs or the 30 inhibition of CyA by cyclosporine A resulted in significant decrease in NS1 secretion without 31 affecting virion release. Using co-localization, co-inmunoprecipitation and proximity ligation 32 assays, NS1 was found to co-localize and interact with all the protein components of the CCC 33 in mosquito infected cells. In addition, CAV-1 and FKBP52 expression was found augmented in 34 DENV infected cells. Finally, the treatment of ZIKV infected mosquito cells with brefeldin A and 35 golgicide A showed no effect on NS1 secretion, while affecting virion release. ZIKV NS1 was 36 also found to co-localize with CAV-1 in infected mosquito cells. These results suggest that in 37 mosquito cells, ZIKV NS1 follows the same secretory pathway observed for DENV NS1. The 38 association of NS1 with the cholesterol transporter CCC agrees with the lipoprotein nature of 39 secreted hexameric NS1. 40 41 AUTHOR SUMMARY . CC-BY 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/370932 doi: bioRxiv preprint 3 42 Dengue protein NS1 is secreted in infected mosquito and vertebrate cells. In humans, secreted 43 NS1 have been associated with pathogenesis. In mosquito cells, NS1 follows an unconventional 44 secretion pathway that is dependent on Caveolin-1. This work shows that in mosquito cells, NS1 45 secretion is associated to the chaperone caveolin complex, a...

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Potential role of cyclophilin A in regulating cytokine secretion

Cited by 73 publications

References 60 publications

Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial

Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial

Global Profiling of PknG Interactions Using a Human Proteome Microarray Reveals Novel Connections with CypA

The dengue virus non-structural protein 1 (NS1) is secreted from mosquito cells in association with the intracellular cholesterol transporter chaperone caveolin complex

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