CD74

CD74
Identifiers
Aliases	CD74, DHLAG, HLADG, II, Ia-GAMMA, CD74 molecule, p33, CLIP
External IDs	OMIM: 142790; MGI: 96534; HomoloGene: 3209; GeneCards: CD74; OMA:CD74 - orthologs
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1A6A, 1ICF, 1IIE, 1L3H, 1MUJ, 3PDO, 3PGC, 3PGD, 3QXA, 3QXD, 4AEN, 4X5W
Gene location (Human) Chr. Chromosome 5 (human) Band 5q33.1 Start 150,401,637 bp End 150,412,969 bp
Gene location (Mouse) Chr. Chromosome 18 (mouse) Band 18 E1|18 34.41 cM Start 60,936,920 bp End 60,945,724 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte appendix granulocyte spleen lymph node right lung gallbladder upper lobe of left lung lower lobe of lung mucosa of ileum Top expressed in spleen jejunum thymus ileum zone of skin colon lip uterus adrenal gland white adipose tissue More reference expression data BioGPS 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 folding chaperone activity MHC class II protein complex binding amyloid-beta binding 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 anatomical structure integral component of lumenal side of endoplasmic reticulum membrane endoplasmic reticulum endoplasmic reticulum membrane plasma 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 cofactor-dependent protein refolding T cell selection 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 cell population 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 protein-containing 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: 60.94 – 60.95 Mb PubMed search
Wikidata
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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. 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. 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).

Structure

The nascent MHC class II protein in the rough endoplasmic reticulum (RER) binds a segment of the invariant chain (Ii; a trimer), which shapes the peptide-binding groove and prevents the formation of a closed conformation. CD74 exists in several isoforms, most commonly p33, p35, p41, and p43, generated by alternative splicing and translation initiation sites. Isoforms p33/35 and p41/43 differ in the length of their luminal domains, with p41 and p43 containing an additional thyroglobulin-like region that influences proteolytic processing and MHC class II antigen presentation. Isoforms p35 and p43 also contain N-terminal extensions that enhance endoplasmic reticulum retention relative to p33 and p41.

Function

The invariant chain facilitates the export of MHC class II molecules from the RER in transport vesicles. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain, directing the complex to late endosomes containing endocytosed antigens from the exogenous pathway. Binding of the invariant chain prevents peptides from the endogenous pathway, which are destined for MHC class I molecules, from occupying the peptide-binding groove of MHC class II molecules.

The invariant chain is subsequently cleaved by cathepsin S (cathepsin L in cortical thymic epithelial cells), leaving only the CLIP fragment bound within the peptide-binding groove of MHC class II molecules, while the remainder of the invariant chain is degraded. CLIP prevents premature peptide binding until HLA-DM catalyzes its release, allowing antigenic peptides to bind. In some cases, CLIP dissociates spontaneously, whereas in others its interaction with MHC class II is sufficiently stable to require HLA-DM-mediated peptide exchange.

The resulting stable MHC class II–antigen complex is then presented on the cell surface for recognition by CD4⁺ T cells. In the absence of CLIP, MHC class II molecules aggregate, dissociate, or denature within endosomes, impairing efficient antigen presentation.

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.

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).

Cancer

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

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).

Interactions

CD74 receptor interacts with the cytokine Macrophage migration inhibitory factor (MIF) to mediate some of its functions.

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.

History

The invariant chain was first described by Patricia P. Jones, Donal B. Murphy, Derek Hewgill, and Hugh McDevitt at Stanford. The nomenclature "Ii" comes from an Ix-based naming system (I for Immune) that predates the naming of the Major Histocompatibility Complex.

See also

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

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): 474–477. 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): 707–716. 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): 839–855. 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): 2589–2594. doi:10.4049/jimmunol.143.8.2589. PMID 2507633. S2CID 6755576.
• 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): 444–460. 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): 53–56. 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): 4484–4488. 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): 6185–6190. 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): 3206–3213. 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): 869–872. 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): 61–69. 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): 2564–2569. doi:10.4049/jimmunol.129.6.2564. PMID 6982931. S2CID 42620266.
• 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): 457–462. 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): 623–629. doi:10.1084/jem.180.2.623. PMC 2191624. PMID 7519244.
• Brown JH, Jardetzky TS, Gorga JC, Stern LJ, Urban RG, Strominger JL, et al. (July 1993). "Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1". Nature. 364 (6432): 33–39. 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): 257–268. 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): 8581–8585. Bibcode:1993PNAS...90.8581R. doi:10.1073/pnas.90.18.8581. PMC 47401. PMID 8397411.

External links

• CD74+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview at Davidson College (student generated)
• School of Crystallography Archived 2023-06-01 at the Wayback Machine The Invariant Chain
• Human CD74 genome location and CD74 gene details page in the UCSC Genome Browser.