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MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations.

Fan C, Rajasekaran D, Syed MA, Leng L, Loria JP, Bhandari V, Bucala R, Lolis EJ
Proc Natl Acad Sci U S A 110 10994-9 (2013)
Cited: 29 times
EuropePMC logo PMID: 23776208

Abstract

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine. In addition to its known receptor-mediated biological activities, MIF possesses a catalytic site of unknown function between subunits of a homotrimer. Each subunit contributes three β-strands to adjacent subunits to form a core seven-stranded β-sheet for each monomer. MIF monomers, dimers, or trimers have been reported, but the active form that binds and activates the MIF receptor (CD74) is still a matter of debate. A cysteine mutant (N110C) that covalently locks MIF into a trimer by forming a disulfide with Cys-80 of an adjacent subunit is used to study this issue. Partial catalytic activity and receptor binding to CD74 are retained by N110C (locked trimer), but there is no cellular signaling. Wild-type MIF-induced cellular signaling, in vivo lung neutrophil accumulation, and alveolar permeability are inhibited with a fivefold excess of N110C. NMR and size-exclusion chromatography with light scattering reveal that N110C can form a higher-order oligomer in equilibrium with a single locked trimer. The X-ray structure confirms a local conformational change that disrupts the subunit interface and results in global changes responsible for the oligomeric form. The structure also confirms these changes are consistent for the partial catalytic and receptor binding activities. The absence of any potential monomer and the retention of partial catalytic and receptor binding activities despite changes in conformation (and dynamics) in the mutant support an endogenous MIF trimer that binds and activates CD74 at nanomolar concentrations. This conclusion has implications for therapeutic development.

Articles - 4gum mentioned but not cited (1)

  1. MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations. Fan C, Rajasekaran D, Syed MA, Leng L, Loria JP, Bhandari V, Bucala R, Lolis EJ. Proc Natl Acad Sci U S A 110 10994-10999 (2013)


Reviews citing this publication (5)

  1. MIF, a controversial cytokine: a review of structural features, challenges, and opportunities for drug development. Bloom J, Sun S, Al-Abed Y. Expert Opin Ther Targets 20 1463-1475 (2016)
  2. Cell Signaling with Extracellular Thioredoxin and Thioredoxin-Like Proteins: Insight into Their Mechanisms of Action. Léveillard T, Aït-Ali N. Oxid Med Cell Longev 2017 8475125 (2017)
  3. Macrophage migration inhibitory factor family proteins are multitasking cytokines in tissue injury. Song S, Xiao Z, Dekker FJ, Poelarends GJ, Melgert BN. Cell Mol Life Sci 79 105 (2022)
  4. CD74 in Kidney Disease. Valiño-Rivas L, Baeza-Bermejillo C, Gonzalez-Lafuente L, Sanz AB, Ortiz A, Sanchez-Niño MD. Front Immunol 6 483 (2015)
  5. Molecular Level Insights Into the Structural and Dynamic Factors Driving Cytokine Function. Cui JY, Lisi GP. Front Mol Biosci 8 773252 (2021)

Articles citing this publication (23)

  1. Cystic fibrosis sputum DNA has NETosis characteristics and neutrophil extracellular trap release is regulated by macrophage migration-inhibitory factor. Dwyer M, Shan Q, D'Ortona S, Maurer R, Mitchell R, Olesen H, Thiel S, Huebner J, Gadjeva M. J Innate Immun 6 765-779 (2014)
  2. Giant tortoise genomes provide insights into longevity and age-related disease. Quesada V, Freitas-Rodríguez S, Miller J, Pérez-Silva JG, Jiang ZF, Tapia W, Santiago-Fernández O, Campos-Iglesias D, Kuderna LFK, Quinzin M, Álvarez MG, Carrero D, Beheregaray LB, Gibbs JP, Chiari Y, Glaberman S, Ciofi C, Araujo-Voces M, Mayoral P, Arango JR, Tamargo-Gómez I, Roiz-Valle D, Pascual-Torner M, Evans BR, Edwards DL, Garrick RC, Russello MA, Poulakakis N, Gaughran SJ, Rueda DO, Bretones G, Marquès-Bonet T, White KP, Caccone A, López-Otín C. Nat Ecol Evol 3 87-95 (2019)
  3. Targeting distinct tautomerase sites of D-DT and MIF with a single molecule for inhibition of neutrophil lung recruitment. Rajasekaran D, Zierow S, Syed M, Bucala R, Bhandari V, Lolis EJ. FASEB J 28 4961-4971 (2014)
  4. MIF inhibits the formation and toxicity of misfolded SOD1 amyloid aggregates: implications for familial ALS. Shvil N, Banerjee V, Zoltsman G, Shani T, Kahn J, Abu-Hamad S, Papo N, Engel S, Bernhagen J, Israelson A. Cell Death Dis 9 107 (2018)
  5. Identification of an Arg-Leu-Arg tripeptide that contributes to the binding interface between the cytokine MIF and the chemokine receptor CXCR4. Lacy M, Kontos C, Brandhofer M, Hille K, Gröning S, Sinitski D, Bourilhon P, Rosenberg E, Krammer C, Thavayogarajah T, Pantouris G, Bakou M, Weber C, Lolis E, Bernhagen J, Kapurniotu A. Sci Rep 8 5171 (2018)
  6. Advances and Insights for Small Molecule Inhibition of Macrophage Migration Inhibitory Factor. Trivedi-Parmar V, Jorgensen WL. J Med Chem 61 8104-8119 (2018)
  7. MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma. Wang Q, Zhao D, Xian M, Wang Z, Bi E, Su P, Qian J, Ma X, Yang M, Liu L, Zu Y, Pingali SR, Chen K, Cai Z, Yi Q. Blood 136 2557-2573 (2020)
  8. Crystallographic and receptor binding characterization of Plasmodium falciparum macrophage migration inhibitory factor complexed to two potent inhibitors. Pantouris G, Rajasekaran D, Baeza Garcia A, Ruiz VG, Leng L, Jorgensen WL, Bucala R, Lolis EJ. J Med Chem 57 8652-8656 (2014)
  9. Modeling of both shared and distinct interactions between MIF and its homologue D-DT with their common receptor CD74. Meza-Romero R, Benedek G, Jordan K, Leng L, Pantouris G, Lolis E, Bucala R, Vandenbark AA. Cytokine 88 62-70 (2016)
  10. Heterocomplexes between the atypical chemokine MIF and the CXC-motif chemokine CXCL4L1 regulate inflammation and thrombus formation. Brandhofer M, Hoffmann A, Blanchet X, Siminkovitch E, Rohlfing AK, El Bounkari O, Nestele JA, Bild A, Kontos C, Hille K, Rohde V, Fröhlich A, Golemi J, Gokce O, Krammer C, Scheiermann P, Tsilimparis N, Sachs N, Kempf WE, Maegdefessel L, Otabil MK, Megens RTA, Ippel H, Koenen RR, Luo J, Engelmann B, Mayo KH, Gawaz M, Kapurniotu A, Weber C, von Hundelshausen P, Bernhagen J. Cell Mol Life Sci 79 512 (2022)
  11. Drug therapy trials for the prevention of bronchopulmonary dysplasia: current and future targets. Bhandari V. Front Pediatr 2 76 (2014)
  12. A structurally preserved allosteric site in the MIF superfamily affects enzymatic activity and CD74 activation in D-dopachrome tautomerase. Chen E, Reiss K, Shah D, Manjula R, Allen B, Murphy EL, Murphy JW, Batista VS, Bhandari V, Lolis EJ, Lisi GP. J Biol Chem 297 101061 (2021)
  13. Attenuation of Macrophage Migration Inhibitory Factor-Stimulated Signaling via S-Nitrosylation. Nakahara K, Fujikawa K, Hiraoka H, Miyazaki I, Asanuma M, Ito A, Takasugi N, Uehara T. Biol Pharm Bull 42 1044-1047 (2019)
  14. Structural basis for decreased induction of class IB PI3-kinases expression by MIF inhibitors. Singh AK, Pantouris G, Borosch S, Rojanasthien S, Cho TY. J Cell Mol Med 21 142-153 (2017)
  15. MIF mediates bladder pain, not inflammation, in cyclophosphamide cystitis. Ma F, Kouzoukas DE, Meyer-Siegler KL, Hunt DE, Leng L, Bucala R, Vera PL. Cytokine X 1 100003 (2019)
  16. Single-Cell RNA-Seq Analysis Reveals Macrophages Are Involved in the Pathogenesis of Human Sporadic Acute Type A Aortic Dissection. Zhang B, Zeng K, Guan RC, Jiang HQ, Qiang YJ, Zhang Q, Yang M, Deng BP, Yang YQ. Biomolecules 13 399 (2023)
  17. Chemokine-like MDL proteins modulate flowering time and innate immunity in plants. Gruner K, Leissing F, Sinitski D, Thieron H, Axstmann C, Baumgarten K, Reinstädler A, Winkler P, Altmann M, Flatley A, Jaouannet M, Zienkiewicz K, Feussner I, Keller H, Coustau C, Falter-Braun P, Feederle R, Bernhagen J, Panstruga R. J Biol Chem 296 100611 (2021)
  18. Treatment with an antigen-specific dual microparticle system reverses advanced multiple sclerosis in mice. Kwiatkowski AJ, Helm EY, Stewart JM, Drashansky TT, Cho JJ, Avram D, Keselowsky BG. Proc Natl Acad Sci U S A 119 e2205417119 (2022)
  19. MIF homolog d-dopachrome tautomerase (D-DT/MIF-2) does not inhibit accumulation and toxicity of misfolded SOD1. Alaskarov A, Barel S, Bakavayev S, Kahn J, Israelson A. Sci Rep 12 9570 (2022)
  20. Macrophage migration inhibitory factor is involved in antineutrophil cytoplasmic antibody-mediated activation of C5a-primed neutrophils. Hao J, Lv T, Xu L, Ran M, Wu K. BMC Immunol 20 22 (2019)
  21. A Cysteine Variant at an Allosteric Site Alters MIF Dynamics and Biological Function in Homo- and Heterotrimeric Assemblies. Skeens E, Pantouris G, Shah D, Manjula R, Ombrello MJ, Maluf NK, Bhandari V, Lisi GP, Lolis EJ. Front Mol Biosci 9 783669 (2022)
  22. Infliximab modifies CD74-mediated lymphatic abnormalities and adipose tissue alterations in creeping fat of Crohn's disease. Shu W, Wang Y, Deji Z, Li C, Chen C, Ding W, Du P, Wang X. Inflamm Res 73 1157-1172 (2024)
  23. Targeting low levels of MIF expression as a potential therapeutic strategy for ALS. Alfahel L, Gschwendtberger T, Kozareva V, Dumas L, Gibbs R, Kertser A, Baruch K, Zaccai S, Kahn J, Thau-Habermann N, Eggenschwiler R, Sterneckert J, Hermann A, Sundararaman N, Vaibhav V, Van Eyk JE, Rafuse VF, Fraenkel E, Cantz T, Petri S, Israelson A. Cell Rep Med 5 101546 (2024)


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