CD74

The nascent MHC class II protein in the rough endoplasmic reticulum (RER) binds a segment of the invariant chain (Ii; a trimer) in order to shape the peptide-binding groove and prevent the formation of a closed conformation.

The invariant chain also facilitates the export of MHC class II from the RER in a vesicle. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. This fuses with a late endosome containing the endocytosed antigen proteins (from the exogenous pathway). Binding to Ii ensures that no antigen peptides from the endogenous pathway meant for MHC class I molecules accidentally bind to the groove of MHC class II molecules.{{cite book | title = Kuby immunology | vauthors = Owen JA, Punt J, Stranford SA, Jones PP, Kuby J | date = 2013 | publisher = W.H. Freeman | isbn = 978-1-4641-1991-0 | edition = 7th | location = New York | oclc = 820117219}} The Ii is then cleaved by cathepsin S (cathepsin L in cortical thymic epithelial cells), leaving only a small fragment called CLIP remaining bound to the groove of MHC class II molecules. The rest of the Ii is degraded. CLIP blocks peptide-binding until HLA-DM interacts with MHC II, releasing CLIP and allowing other peptides to bind. In some cases, CLIP dissociates without any further molecular interactions, but in other cases the binding to the MHC is more stable.{{cite journal | vauthors = Schulze MS, Wucherpfennig KW | title = The mechanism of HLA-DM induced peptide exchange in the MHC class II antigen presentation pathway | journal = Current Opinion in Immunology | volume = 24 | issue = 1 | pages = 105–111 | date = February 2012 | pmid = 22138314 | pmc = 3288754 | doi = 10.1016/j.coi.2011.11.004 }}

The stable MHC class II + antigen complex is then presented on the cell surface. Without CLIP, MHC class II aggregates disassemble and/or denature in the endosomes, and proper antigen presentation is impaired.{{cite journal | vauthors = Vogt AB, Kropshofer H | title = HLA-DM - an endosomal and lysosomal chaperone for the immune system | journal = Trends in Biochemical Sciences | volume = 24 | issue = 4 | pages = 150–154 | date = April 1999 | pmid = 10322421 | doi = 10.1016/s0968-0004(99)01364-x }}

The Ii molecule—fused with a viral vector to a conserved region of the Hepatitis C virus (HCV) genome—has been tested as an adjuvant for a HCV vaccine in a cohort of 17 healthy human volunteers. This experimental vaccine was well-tolerated, and those who received the adjuvanted vaccine had stronger anti-HCV immune responses (enhanced magnitude, breadth and proliferative capacity of anti-HCV-specific T-cells) compared with volunteers who received the vaccine that lacked the Ii adjuvant.{{cite journal | vauthors = Esposito I, Cicconi P, D'Alise AM, Brown A, Esposito M, Swadling L, Holst PJ, Bassi MR, Stornaiuolo M, Mori F, Vassilev V, Li W, Donnison T, Gentile C, Turner B, von Delft A, Del Sorbo M, Barra F, Contino AM, Abbate A, Novellino E, Thomsen AR, Christensen JP, Lahm A, Grazioli F, Ammendola V, Siani L, Colloca S, Klenerman P, Nicosia A, Dorrell L, Folgori A, Capone S, Barnes E | display-authors = 6 | title = MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans | journal = Science Translational Medicine | volume = 12 | issue = 548 | pages = eaaz7715 | date = June 2020 | pmid = 32554708 | pmc = 7610808 | doi = 10.1126/scitranslmed.aaz7715 | s2cid = 219722045 }}

The Ii molecule might also prove to be useful as an adjuvant for a future vaccine for the SARS-CoV-2 virus, if this enhancing effect can be demonstrated to apply to the appropriate antigen(s).{{cite web| vauthors = Larkin M |title=Adjuvanted viral-vectored vaccine promising against hepatitis C in early trial|work=Reuters Health News|publisher=GI Health Foundation|date=June 24, 2020|url=https://www.gihealthfoundation.org/reuters/article.cfm?article=20200624Other669656573&cat=Othe&dstate=GI|access-date=Aug 10, 2020}}

Found on a number of cancer cell types. Possible cancer therapy target. See milatuzumab.

Autoantibodies against CD74 have been identified as promising biomarkers in the early diagnosis of the autoimmune disease called axial spondyloarthritis (non-radiographic axial spondyloarthritis and radiographic axial spondyloarthritis / Ankylosing spondylitis). {{cite journal | vauthors = Baerlecken NT, Nothdorft S, Stummvoll GH, Sieper J, Rudwaleit M, Reuter S, Matthias T, Schmidt RE, Witte T | display-authors = 6 | title = Autoantibodies against CD74 in spondyloarthritis | journal = Annals of the Rheumatic Diseases | volume = 73 | issue = 6 | pages = 1211–1214 | date = June 2014 | pmid = 23687263 | doi = 10.1136/annrheumdis-2012-202208 | s2cid = 22939188 }}

CD74 receptor interacts with the cytokine Macrophage migration inhibitory factor (MIF) to mediate some of its functions.{{cite journal | vauthors = Ghosh S, Padalia J, Ngobeni R, Abendroth J, Farr L, Shirley DA, Edwards T, Moonah S | display-authors = 6 | title = Targeting Parasite-Produced Macrophage Migration Inhibitory Factor as an Antivirulence Strategy With Antibiotic-Antibody Combination to Reduce Tissue Damage | journal = The Journal of Infectious Diseases | volume = 221 | issue = 7 | pages = 1185–1193 | date = March 2020 | pmid = 31677380 | pmc = 7325720 | doi = 10.1093/infdis/jiz579 | doi-access = free }}

{{cite journal | vauthors = Shan ZX, Lin QX, Deng CY, Tan HH, Kuang SJ, Xiao DZ, Zhu JN, Fu YH, Yu XY | display-authors = 6 | title = [Identification of the interactions between the truncated fragments of macrophage migration inhibitory factor and CD74 using a yeast two-hybrid system] | language = zh | journal = Nan Fang Yi Ke da Xue Xue Bao = Journal of Southern Medical University | volume = 29 | issue = 12 | pages = 2383–6, 2390 | date = December 2009 | pmid = 20034881 }}{{cite journal | vauthors = Wang F, Shen X, Guo X, Peng Y, Liu Y, Xu S, Yang J | title = Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats | journal = Pain | volume = 148 | issue = 2 | pages = 275–283 | date = February 2010 | pmid = 20005040 | doi = 10.1016/j.pain.2009.11.011 | s2cid = 38141283 }}{{cite journal | vauthors = Dobson SE, Augustijn KD, Brannigan JA, Schnick C, Janse CJ, Dodson EJ, Waters AP, Wilkinson AJ | display-authors = 6 | title = The crystal structures of macrophage migration inhibitory factor from Plasmodium falciparum and Plasmodium berghei | journal = Protein Science | volume = 18 | issue = 12 | pages = 2578–2591 | date = December 2009 | pmid = 19827093 | pmc = 2798171 | doi = 10.1002/pro.263 }}{{cite journal | vauthors = Piette C, Deprez M, Roger T, Noël A, Foidart JM, Munaut C | title = The dexamethasone-induced inhibition of proliferation, migration, and invasion in glioma cell lines is antagonized by macrophage migration inhibitory factor (MIF) and can be enhanced by specific MIF inhibitors | journal = The Journal of Biological Chemistry | volume = 284 | issue = 47 | pages = 32483–32492 | date = November 2009 | pmid = 19759012 | pmc = 2781663 | doi = 10.1074/jbc.M109.014589 | doi-access = free }}{{cite journal | vauthors = Verjans E, Noetzel E, Bektas N, Schütz AK, Lue H, Lennartz B, Hartmann A, Dahl E, Bernhagen J | display-authors = 6 | title = Dual role of macrophage migration inhibitory factor (MIF) in human breast cancer | journal = BMC Cancer | volume = 9 | pages = 230 | date = July 2009 | pmid = 19602265 | pmc = 2716369 | doi = 10.1186/1471-2407-9-230 | doi-access = free }}

File:Role of CD74 receptor in tissue injury and wound repair.png

CD74 receptor is expressed on the surface of different cell types. Interaction between MIF cytokine and its cell membrane receptor CD74 activates pro-survival and proliferative pathways that protect against injury and promote healing in different parts of the body.{{cite journal | vauthors = Farr L, Ghosh S, Moonah S | title = Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair | journal = Frontiers in Immunology | volume = 11 | pages = 1273 | date = 2020 | pmid = 32655566 | pmc = 7325688 | doi = 10.3389/fimmu.2020.01273 | doi-access = free }}

The invariant chain was first described by Patricia P. Jones, Donal B. Murphy, Derek Hewgill, and Hugh McDevitt at Stanford.{{cite journal | vauthors = Jones PP, Murphy DB, Hewgill D, McDevitt HO | title = Detection of a common polypeptide chain in I--A and I--E sub-region immunoprecipitates | journal = Molecular Immunology | volume = 16 | issue = 1 | pages = 51–60 | date = January 1979 | pmid = 376435 | doi = 10.1016/0161-5890(79)90027-0 }} The nomenclature "Ii" comes from an Ix-based naming system (I for {{not a typo|Immune}}) that predates the naming of the Major Histocompatibility Complex.

• Cluster of differentiation
• Milatuzumab the first Mab to target CD74

{{Reflist}}

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• {{cite journal | vauthors = Riberdy JM, Newcomb JR, Surman MJ, Barbosa JA, Cresswell P | title = HLA-DR molecules from an antigen-processing mutant cell line are associated with invariant chain peptides | journal = Nature | volume = 360 | issue = 6403 | pages = 474–477 | date = December 1992 | pmid = 1448172 | doi = 10.1038/360474a0 | s2cid = 4338656 | bibcode = 1992Natur.360..474R }}
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• {{cite journal | vauthors = Spiro RC, Quaranta V | title = The invariant chain is a phosphorylated subunit of class II molecules | journal = Journal of Immunology | volume = 143 | issue = 8 | pages = 2589–2594 | date = October 1989 | doi = 10.4049/jimmunol.143.8.2589 | pmid = 2507633 | s2cid = 6755576 | doi-access = free }}
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• {{cite journal | vauthors = Claesson L, Peterson PA | title = Association of human gamma chain with class II transplantation antigens during intracellular transport | journal = Biochemistry | volume = 22 | issue = 13 | pages = 3206–3213 | date = June 1983 | pmid = 6576808 | doi = 10.1021/bi00282a026 }}
• {{cite journal | vauthors = Strubin M, Mach B, Long EO | title = The complete sequence of the mRNA for the HLA-DR-associated invariant chain reveals a polypeptide with an unusual transmembrane polarity | journal = The EMBO Journal | volume = 3 | issue = 4 | pages = 869–872 | date = April 1984 | pmid = 6586420 | pmc = 557440 | doi = 10.1002/j.1460-2075.1984.tb01898.x }}
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• {{cite journal | vauthors = Machamer CE, Cresswell P | title = Biosynthesis and glycosylation of the invariant chain associated with HLA-DR antigens | journal = Journal of Immunology | volume = 129 | issue = 6 | pages = 2564–2569 | date = December 1982 | doi = 10.4049/jimmunol.129.6.2564 | pmid = 6982931 | s2cid = 42620266 }}
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• {{cite journal | vauthors = Bijlmakers MJ, Benaroch P, Ploegh HL | title = Mapping functional regions in the lumenal domain of the class II-associated invariant chain | journal = The Journal of Experimental Medicine | volume = 180 | issue = 2 | pages = 623–629 | date = August 1994 | pmid = 7519244 | pmc = 2191624 | doi = 10.1084/jem.180.2.623 }}
• {{cite journal | vauthors = Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC | title = Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1 | journal = Nature | volume = 364 | issue = 6432 | pages = 33–39 | date = July 1993 | pmid = 8316295 | doi = 10.1038/364033a0 | s2cid = 4248668 | bibcode = 1993Natur.364...33B }}
• {{cite journal | vauthors = Naujokas MF, Morin M, Anderson MS, Peterson M, Miller J | title = The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44 | journal = Cell | volume = 74 | issue = 2 | pages = 257–268 | date = July 1993 | pmid = 8343954 | doi = 10.1016/0092-8674(93)90417-O | s2cid = 10295196 }}
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{{refend}}

• {{MeshName|CD74+protein,+human}}
• [http://www.bio.davidson.edu/Courses/immunology/Students/spring2006/McCracken/HLA-DM.html Overview] at Davidson College (student generated)
• [http://www.cryst.bbk.ac.uk/pps97/assignments/projects/coadwell/007.htm School of Crystallography] The Invariant Chain
• {{UCSC gene info|CD74}}

{{PDB Gallery|geneid=972}}

{{Clusters of differentiation}}

{{DEFAULTSORT:Cd74}}

Category:Clusters of differentiation

Category:Immune system