CD74

HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74 (Cluster of Differentiation 74), is a protein that in humans is encoded by the CD74 gene.[5][6] The invariant chain (Abbreviated Ii) is a polypeptide which plays a critical role in antigen presentation. It is involved in the formation and transport of MHC class II peptide complexes for the generation of CD4+ T cell responses.[7][8] The cell surface form of the invariant chain is known as CD74. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF).[9]

CD74
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1A6A, 1ICF, 1IIE, 1L3H, 1MUJ, 3PDO, 3PGC, 3PGD, 3QXA, 3QXD, 4AEN, 4X5W
Identifiers
Aliases	CD74, DHLAG, HLADG, II, Ia-GAMMA, CD74 molecule, p33
External IDs	OMIM: 142790 MGI: 96534 HomoloGene: 3209 GeneCards: CD74
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q33.1 Start 150,400,041 bp[1] End 150,412,929 bp[1]
Gene location (Mouse) Chr. Chromosome 18 (mouse)[2] Band 18 E1|18 34.41 cM Start 60,803,848 bp[2] End 60,812,652 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • nitric-oxide synthase binding • identical protein binding • MHC class II protein binding, via antigen binding groove • cytokine receptor activity • macrophage migration inhibitory factor binding • protein binding involved in protein folding • MHC class II protein complex binding • amyloid-beta binding • GO:0001948 protein binding • MHC class II protein binding • cytokine binding • CD4 receptor binding Cellular component • lysosomal lumen • extracellular exosome • MHC class II protein complex • lysosomal membrane • late endosome • endocytic vesicle membrane • transport vesicle membrane • integral component of membrane • ER to Golgi transport vesicle membrane • multivesicular body • Golgi apparatus • Golgi membrane • trans-Golgi network membrane • macrophage migration inhibitory factor receptor complex • membrane • cell surface • intracellular • integral component of lumenal side of endoplasmic reticulum membrane • endoplasmic reticulum • endoplasmic reticulum membrane • cell membrane • lysosome • vacuole • endosome • clathrin-coated endocytic vesicle membrane • NOS2-CD74 complex • external side of plasma membrane Biological process • immune response • positive regulation of T cell differentiation • negative regulation of apoptotic process • signal transduction • positive thymic T cell selection • chaperone mediated protein folding requiring cofactor • T cell selection • activation of MAPK activity • positive regulation of type 2 immune response • positive regulation of dendritic cell antigen processing and presentation • antigen processing and presentation of exogenous peptide antigen via MHC class II • adaptive immune response • antigen processing and presentation • positive regulation of peptidyl-tyrosine phosphorylation • negative regulation of mature B cell apoptotic process • regulation of macrophage activation • negative regulation of DNA damage response, signal transduction by p53 class mediator • immunoglobulin mediated immune response • leukocyte migration • positive regulation of neutrophil chemotaxis • positive regulation of chemokine (C-X-C motif) ligand 2 production • macrophage migration inhibitory factor signaling pathway • prostaglandin biosynthetic process • cellular proliferation • antigen processing and presentation of endogenous antigen • immune system process • defense response • negative regulation of peptide secretion • negative regulation of T cell differentiation • positive regulation of macrophage cytokine production • positive regulation of B cell proliferation • negative thymic T cell selection • positive regulation of fibroblast proliferation • intracellular protein transport • positive regulation of ERK1 and ERK2 cascade • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • positive regulation of cytokine-mediated signaling pathway • positive regulation of protein phosphorylation • positive regulation of kinase activity • positive regulation of I-kappaB kinase/NF-kappaB signaling • positive regulation of MAPK cascade • positive regulation of monocyte differentiation • positive regulation of transcription, DNA-templated • positive regulation of viral entry into host cell • protein heterotetramerization • protein trimerization • macromolecular complex assembly Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	972	16149
Ensembl	ENSG00000019582	ENSMUSG00000024610
UniProt	P04233	P04441
RefSeq (mRNA)	NM_004355 NM_001025158 NM_001025159 NM_001364083 NM_001364084	NM_001042605 NM_010545
RefSeq (protein)	NP_001020329 NP_001020330 NP_004346 NP_001351012 NP_001351013	NP_001036070 NP_034675
Location (UCSC)	Chr 5: 150.4 – 150.41 Mb	Chr 18: 60.8 – 60.81 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

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.[10] 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.[10] 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.[11]

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.[12]

Clinical significance

Vaccine adjuvant

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.[13]

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).[14]

Cancer

Found on a number of cancer cell types. Possible cancer therapy target. See Milatuzumab#CD74

Axial spondyloarthritis

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). [15]

Interactions

CD74 receptor interacts with the cytokine Macrophage migration inhibitory factor (MIF) to mediate some of its functions.[16][17][18][19][20][21]

Recovery functions

Role of CD74 receptor in tissue injury and wound repair

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.[22]

See also

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

References

1. GRCh38: Ensembl release 89: ENSG00000019582 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024610 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Claesson L, Larhammar D, Rask L, Peterson PA (December 1983). "cDNA clone for the human invariant gamma chain of class II histocompatibility antigens and its implications for the protein structure". Proceedings of the National Academy of Sciences of the United States of America. 80 (24): 7395–9. Bibcode:1983PNAS...80.7395C. doi:10.1073/pnas.80.24.7395. PMC 389957. PMID 6324166.
6. Kudo J, Chao LY, Narni F, Saunders GF (December 1985). "Structure of the human gene encoding the invariant gamma-chain of class II histocompatibility antigens". Nucleic Acids Research. 13 (24): 8827–41. doi:10.1093/nar/13.24.8827. PMC 318954. PMID 3001652.
7. "UniProtKB - P04233 (HG2A_HUMAN)". The UniProt Knowledgebase. The UniProt Consortium. 2020. Retrieved Aug 10, 2020.
8. Cresswell P (1994). "Assembly, transport, and function of MHC class II molecules". Annual Review of Immunology. 12: 259–93. doi:10.1146/annurev.iy.12.040194.001355. PMID 8011283.
9. Farr L, Ghosh S, Moonah S (2020). "Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair". Frontiers in Immunology. 11: 1273. doi:10.3389/fimmu.2020.01273. PMC 7325688. PMID 32655566.
10. Owen JA, Punt J, Stranford SA, Jones PP, Kuby J (2013). Kuby immunology (7th ed.). New York: W.H. Freeman. ISBN 978-1-4641-1991-0. OCLC 820117219.
11. Schulze MS, Wucherpfennig KW (February 2012). "The mechanism of HLA-DM induced peptide exchange in the MHC class II antigen presentation pathway". Current Opinion in Immunology. 24 (1): 105–11. doi:10.1016/j.coi.2011.11.004. PMC 3288754. PMID 22138314.
12. Vogt AB, Kropshofer H (April 1999). "HLA-DM - an endosomal and lysosomal chaperone for the immune system". Trends in Biochemical Sciences. 24 (4): 150–4. doi:10.1016/s0968-0004(99)01364-x. PMID 10322421.
13. Esposito I, Cicconi P, D'Alise AM, Brown A, Esposito M, Swadling L, et al. (June 2020). "MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans". Science Translational Medicine. 12 (548): eaaz7715. doi:10.1126/scitranslmed.aaz7715. PMID 32554708. S2CID 219722045.
14. Larkin, M (June 24, 2020). "Adjuvanted viral-vectored vaccine promising against hepatitis C in early trial". Reuters Health News. GI Health Foundation. Retrieved Aug 10, 2020.
15. Baerlecken NT, Nothdorft S, Stummvoll GH, Sieper J, Rudwaleit M, Reuter S, et al. (June 2014). "Autoantibodies against CD74 in spondyloarthritis". Annals of the Rheumatic Diseases. 73 (6): 1211–4. doi:10.1136/annrheumdis-2012-202208. PMID 23687263. S2CID 22939188.
16. Ghosh S, Padalia J, Ngobeni R, Abendroth J, Farr L, Shirley DA, et al. (March 2020). "Targeting Parasite-Produced Macrophage Migration Inhibitory Factor as an Antivirulence Strategy With Antibiotic-Antibody Combination to Reduce Tissue Damage". The Journal of Infectious Diseases. 221 (7): 1185–1193. doi:10.1093/infdis/jiz579. PMC 7325720. PMID 31677380.
17. Shan ZX, Lin QX, Deng CY, Tan HH, Kuang SJ, Xiao DZ, et al. (December 2009). "[Identification of the interactions between the truncated fragments of macrophage migration inhibitory factor and CD74 using a yeast two-hybrid system]". Nan Fang Yi Ke da Xue Xue Bao = Journal of Southern Medical University (in Chinese). 29 (12): 2383–6, 2390. PMID 20034881.
18. Wang F, Shen X, Guo X, Peng Y, Liu Y, Xu S, Yang J (February 2010). "Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats". Pain. 148 (2): 275–83. doi:10.1016/j.pain.2009.11.011. PMID 20005040. S2CID 38141283.
19. Dobson SE, Augustijn KD, Brannigan JA, Schnick C, Janse CJ, Dodson EJ, et al. (December 2009). "The crystal structures of macrophage migration inhibitory factor from Plasmodium falciparum and Plasmodium berghei". Protein Science. 18 (12): 2578–91. doi:10.1002/pro.263. PMC 2798171. PMID 19827093.
20. Piette C, Deprez M, Roger T, Noël A, Foidart JM, Munaut C (November 2009). "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". The Journal of Biological Chemistry. 284 (47): 32483–92. doi:10.1074/jbc.M109.014589. PMC 2781663. PMID 19759012.
21. Verjans E, Noetzel E, Bektas N, Schütz AK, Lue H, Lennartz B, et al. (July 2009). "Dual role of macrophage migration inhibitory factor (MIF) in human breast cancer". BMC Cancer. 9: 230. doi:10.1186/1471-2407-9-230. PMC 2716369. PMID 19602265.
22. Farr L, Ghosh S, Moonah S (2020). "Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair". Frontiers in Immunology. 11: 1273. doi:10.3389/fimmu.2020.01273. PMC 7325688. PMID 32655566.

Further reading

• Stove V, Verhasselt B (January 2006). "Modelling thymic HIV-1 Nef effects". Current HIV Research. 4 (1): 57–64. doi:10.2174/157016206775197583. PMID 16454711.
• Riberdy JM, Newcomb JR, Surman MJ, Barbosa JA, Cresswell P (December 1992). "HLA-DR molecules from an antigen-processing mutant cell line are associated with invariant chain peptides". Nature. 360 (6403): 474–7. Bibcode:1992Natur.360..474R. doi:10.1038/360474a0. PMID 1448172. S2CID 4338656.
• Bakke O, Dobberstein B (November 1990). "MHC class II-associated invariant chain contains a sorting signal for endosomal compartments" (PDF). Cell. 63 (4): 707–16. doi:10.1016/0092-8674(90)90137-4. PMID 2121367. S2CID 19993336.
• Marks MS, Blum JS, Cresswell P (September 1990). "Invariant chain trimers are sequestered in the rough endoplasmic reticulum in the absence of association with HLA class II antigens". The Journal of Cell Biology. 111 (3): 839–55. doi:10.1083/jcb.111.3.839. PMC 2116304. PMID 2391366.
• Spiro RC, Quaranta V (October 1989). "The invariant chain is a phosphorylated subunit of class II molecules". Journal of Immunology. 143 (8): 2589–94. PMID 2507633.
• O'Sullivan DM, Noonan D, Quaranta V (August 1987). "Four Ia invariant chain forms derive from a single gene by alternate splicing and alternate initiation of transcription/translation". The Journal of Experimental Medicine. 166 (2): 444–60. doi:10.1084/jem.166.2.444. PMC 2189580. PMID 3036998.
• Genuardi M, Saunders GF (1988). "Localization of the HLA class II-associated invariant chain gene to human chromosome band 5q32". Immunogenetics. 28 (1): 53–6. doi:10.1007/BF00372530. PMID 3132422. S2CID 2418453.
• O'Sullivan DM, Larhammar D, Wilson MC, Peterson PA, Quaranta V (June 1986). "Structure of the human Ia-associated invariant (gamma)-chain gene: identification of 5' sequences shared with major histocompatibility complex class II genes". Proceedings of the National Academy of Sciences of the United States of America. 83 (12): 4484–8. Bibcode:1986PNAS...83.4484O. doi:10.1073/pnas.83.12.4484. PMC 323758. PMID 3459184.
• Koch N, Hämmerling GJ (October 1985). "Ia-associated invariant chain is fatty acylated before addition of sialic acid". Biochemistry. 24 (22): 6185–90. doi:10.1021/bi00343a023. PMID 3866610.
• Claesson L, Peterson PA (June 1983). "Association of human gamma chain with class II transplantation antigens during intracellular transport". Biochemistry. 22 (13): 3206–13. doi:10.1021/bi00282a026. PMID 6576808.
• Strubin M, Mach B, Long EO (April 1984). "The complete sequence of the mRNA for the HLA-DR-associated invariant chain reveals a polypeptide with an unusual transmembrane polarity". The EMBO Journal. 3 (4): 869–72. doi:10.1002/j.1460-2075.1984.tb01898.x. PMC 557440. PMID 6586420.
• Kvist S, Wiman K, Claesson L, Peterson PA, Dobberstein B (May 1982). "Membrane insertion and oligomeric assembly of HLA-DR histocompatibility antigens" (PDF). Cell. 29 (1): 61–9. doi:10.1016/0092-8674(82)90090-3. PMID 6955026. S2CID 9066996.
• Machamer CE, Cresswell P (December 1982). "Biosynthesis and glycosylation of the invariant chain associated with HLA-DR antigens". Journal of Immunology. 129 (6): 2564–9. PMID 6982931.
• Ghosh P, Amaya M, Mellins E, Wiley DC (November 1995). "The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3". Nature. 378 (6556): 457–62. Bibcode:1995Natur.378..457G. doi:10.1038/378457a0. PMID 7477400. S2CID 4275956.
• Bijlmakers MJ, Benaroch P, Ploegh HL (August 1994). "Mapping functional regions in the lumenal domain of the class II-associated invariant chain". The Journal of Experimental Medicine. 180 (2): 623–9. doi:10.1084/jem.180.2.623. PMC 2191624. PMID 7519244.
• Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC (July 1993). "Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1". Nature. 364 (6432): 33–9. Bibcode:1993Natur.364...33B. doi:10.1038/364033a0. PMID 8316295. S2CID 4248668.
• Naujokas MF, Morin M, Anderson MS, Peterson M, Miller J (July 1993). "The chondroitin sulfate form of invariant chain can enhance stimulation of T cell responses through interaction with CD44". Cell. 74 (2): 257–68. doi:10.1016/0092-8674(93)90417-O. PMID 8343954. S2CID 10295196.
• Roche PA, Teletski CL, Stang E, Bakke O, Long EO (September 1993). "Cell surface HLA-DR-invariant chain complexes are targeted to endosomes by rapid internalization". Proceedings of the National Academy of Sciences of the United States of America. 90 (18): 8581–5. Bibcode:1993PNAS...90.8581R. doi:10.1073/pnas.90.18.8581. PMC 47401. PMID 8397411.

External links

• CD74+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
• Overview at Davidson College (student generated)
• School of Crystallography The Invariant Chain
• Human CD74 genome location and CD74 gene details page in the UCSC Genome Browser.