scholarly journals Mannose Binding Lectin Is Hydroxylated by Collagen Prolyl-4-hydroxylase and Inhibited by Some PHD Inhibitors

Kidney360 ◽  
2020 ◽  
Vol 1 (6) ◽  
pp. 447-457
Author(s):  
Vijesh J. Bhute ◽  
James Harte ◽  
Jack W. Houghton ◽  
Patrick H. Maxwell

BackgroundMannose-binding lectin (MBL) is an important component of innate immune defense. MBL undergoes oligomerization to generate high mol weight (HMW) forms which act as pattern recognition molecules to detect and opsonize various microorganisms. Several post-translational modifications including prolyl hydroxylation are known to affect the oligomerization of MBL. Yet, the enzyme(s) which hydroxylate proline in the collagen-like domain residues have not been identified and the significance of prolyl hydroxylation is incompletely understood.MethodsTo investigate post-translational modifications of MBL, we stably expressed Myc-DDK tagged MBL in HEK293S cells. We used pharmacologic and genetic inhibition of 2-oxoglutarate–dependent dioxygenases (2OGDD) to identify the enzyme required for prolyl hydroxylation of MBL. We performed mass spectrometry to determine the effects of various inhibitors on MBL modifications.ResultsSecretion of HMW MBL was impaired by inhibitors of the superfamily of 2OGDD, and was dependent on prolyl-4-hydroxylase subunit α1. Roxadustat and vadadustat, but not molidustat, led to significant suppression of hydroxylation and secretion of HMW forms of MBL.ConclusionsThese data suggest that prolyl hydroxylation in the collagen-like domain of MBL is mediated by collagen prolyl-4-hydroxylase. Reduced MBL activity is likely to be an off-target effect of some, but not all, prolyl hydroxylase domain (PHD) inhibitors. There may be advantages in selective PHD inhibitors that would not interfere with MBL production.

2008 ◽  
Vol 205 (1) ◽  
pp. 169-181 ◽  
Author(s):  
W.K. Eddie Ip ◽  
Kazue Takahashi ◽  
Kathryn J. Moore ◽  
Lynda M. Stuart ◽  
R. Alan B. Ezekowitz

Innate immunity is the first-line defense against pathogens and relies on phagocytes, soluble components, and cell-surface and cytosolic pattern recognition receptors. Despite using hard-wired receptors and signaling pathways, the innate immune response demonstrates surprising specificity to different pathogens. We determined how combinatorial use of innate immune defense mechanisms defines the response. We describe a novel cooperation between a soluble component of the innate immune system, the mannose-binding lectin, and Toll-like receptor 2 that both specifies and amplifies the host response to Staphylococcus aureus. Furthermore, we demonstrate that this cooperation occurs within the phagosome, emphasizing the importance of engulfment in providing the appropriate cellular environment to facilitate the synergy between these defense pathways.


2008 ◽  
Vol 60 (4) ◽  
pp. 333-345 ◽  
Author(s):  
Nandor Gabor Than ◽  
Roberto Romero ◽  
Offer Erez ◽  
Juan Pedro Kusanovic ◽  
Adi L. Tarca ◽  
...  

2016 ◽  
Vol 90 (11) ◽  
pp. 5256-5269 ◽  
Author(s):  
Anne-Laure Favier ◽  
Evelyne Gout ◽  
Olivier Reynard ◽  
Olivier Ferraris ◽  
Jean-Philippe Kleman ◽  
...  

ABSTRACTEbola virus infection requires the surface viral glycoprotein to initiate entry into the target cells. The trimeric glycoprotein is a highly glycosylated viral protein which has been shown to interact with host C-type lectin receptors and the soluble complement recognition protein mannose-binding lectin, thereby enhancing viral infection. Similarly to mannose-binding lectin, ficolins are soluble effectors of the innate immune system that recognize particular glycans at the pathogen surface. In this study, we demonstrate that ficolin-1 interacts with the Zaire Ebola virus (EBOV) glycoprotein, and we characterized this interaction by surface plasmon resonance spectroscopy. Ficolin-1 was shown to bind to the viral glycoprotein with a high affinity. This interaction was mediated by the fibrinogen-like recognition domain of ficolin-1 and the mucin-like domain of the viral glycoprotein. Using a ficolin-1 control mutant devoid of sialic acid-binding capacity, we identified sialylated moieties of the mucin domain to be potential ligands on the glycoprotein. In cell culture, using both pseudotyped viruses and EBOV, ficolin-1 was shown to enhance EBOV infection independently of the serum complement. We also observed that ficolin-1 enhanced EBOV infection on human monocyte-derived macrophages, described to be major viral target cells,. Competition experiments suggested that although ficolin-1 and mannose-binding lectin recognized different carbohydrate moieties on the EBOV glycoprotein, the observed enhancement of the infection likely depended on a common cellular receptor/partner. In conclusion, ficolin-1 could provide an alternative receptor-mediated mechanism for enhancing EBOV infection, thereby contributing to viral subversion of the host innate immune system.IMPORTANCEA specific interaction involving ficolin-1 (M-ficolin), a soluble effector of the innate immune response, and the glycoprotein (GP) of EBOV was identified. Ficolin-1 enhanced virus infection instead of tipping the balance toward its elimination. An interaction between the fibrinogen-like recognition domain of ficolin-1 and the mucin-like domain of Ebola virus GP occurred. In this model, the enhancement of infection was shown to be independent of the serum complement. The facilitation of EBOV entry into target host cells by the interaction with ficolin-1 and other host lectins shunts virus elimination, which likely facilitates the survival of the virus in infected host cells and contributes to the virus strategy to subvert the innate immune response.


2004 ◽  
Vol 279 (31) ◽  
pp. 32728-32736 ◽  
Author(s):  
Nades Palaniyar ◽  
Jeya Nadesalingam ◽  
Howard Clark ◽  
Michael J. Shih ◽  
Alister W. Dodds ◽  
...  

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Bojan Nedovic ◽  
Brunella Posteraro ◽  
Emanuele Leoncini ◽  
Alberto Ruggeri ◽  
Rosarita Amore ◽  
...  

Mannose-binding lectin (MBL) plays a key role in the human innate immune response. It has been shown that polymorphisms in theMBL2gene, particularly at codon 54 (variant alleleB; wild-type allele designated asA), impact upon host susceptibility toCandidainfection. This systematic review and meta-analysis were performed to assess the association betweenMBL2codon 54 genotype and vulvovaginal candidiasis (VVC) or recurrent VVC (RVVC). Studies were searched in MEDLINE, SCOPUS, and ISI Web of Science until April 2013. Five studies including 704 women (386 cases and 318 controls) were part of the meta-analysis, and pooled ORs were calculated using the random effects model. For subjects with RVVC, ORs ofABversusAAand ofBBversusAAwere 4.84 (95% CI 2.10–11.15;Pfor heterogeneity=0.013;I2=68.6%) and 12.68 (95% CI 3.74–42.92;Pfor heterogeneity=0.932,I2=0.0%), respectively. For subjects with VVC, OR ofABversusAAwas 2.57 (95% CI 1.29–5.12;Pfor heterogeneity=0.897;I2=0.0%). This analysis indicates that heterozygosity for theMBL2alleleBincreases significantly the risk for both diseases, suggesting that MBL may influence the women’s innate immunity in response toCandida.


2000 ◽  
Vol 68 (2) ◽  
pp. 688-693 ◽  
Author(s):  
Olaf Neth ◽  
Dominic L. Jack ◽  
Alister W. Dodds ◽  
Helen Holzel ◽  
Nigel J. Klein ◽  
...  

ABSTRACT Mannose-binding lectin (MBL) is a collagenous serum lectin believed to be of importance in innate immunity. Genetically determined low levels of the protein are known to predispose to infections. In this study the binding of purified MBL to pathogens isolated from immunocompromised children was investigated by flow cytometry. DiverseCandida species, Aspergillus fumigatus,Staphylococcus aureus, and beta-hemolytic group A streptococci exhibited strong binding of MBL, whereas Escherichia coli, Klebsiella species, and Haemophilus influenzae type b were characterized by heterogeneous binding patterns. In contrast, beta-hemolytic group B streptococci,Streptococcus pneumoniae, and Staphylococcus epidermidis showed low levels of binding. Bound MBL was able to promote C4 deposition in a concentration-dependent manner. We conclude that MBL may be of importance in first-line immune defense against several important pathogens.


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