CD74

CD74
Available structures PDB Ortholog search:PDBeRCSB 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, CLIP
External IDs	OMIM:142790;MGI:96534;HomoloGene:3209;GeneCards:CD74;OMA:CD74 - orthologs
Gene location (Human) Chr. Chromosome 5 (human) Band 5q33.1 Start 150,401,637bp End 150,412,969bp
Gene location (Mouse) Chr. Chromosome 18 (mouse) Band 18 E1|18 34.41 cM Start 60,936,920bp End 60,945,724bp
RNA expressionpattern 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 PubMedsearch
Wikidata
View/Edit Human View/Edit Mouse

HLA class II histocompatibility antigen gamma chainalso known asHLA-DR antigens-associated invariant chainorCD74(Cluster ofDifferentiation 74), is aproteinthat in humans is encoded by theCD74gene.Theinvariant chain(AbbreviatedIi) is apolypeptidewhich plays a critical role inantigen presentation.It is involved in the formation and transport ofMHC class IIpeptide complexes for the generation ofCD4+ T cellresponses.The cell surface form of the invariant chain is known as CD74. CD74 is acell surface receptorfor the cytokinemacrophage migration inhibitory factor(MIF).

Function

The nascentMHCclass II protein in therough 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 lateendosomecontaining the endocytosed antigen proteins (from the exogenous pathway). Binding to Ii ensures that no antigen peptides from the endogenous pathway meant forMHC class Imolecules accidentally bind to the groove of MHC class II molecules.The Ii is then cleaved bycathepsin S(cathepsin Lincortical thymic epithelial cells), leaving only a small fragment calledCLIPremaining bound to the groove of MHC class II molecules. The rest of the Ii is degraded.CLIP blocks peptide-binding untilHLA-DMinteracts 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.

The stable MHC class II + antigen complex is thenpresentedon the cell surface. Without CLIP, MHC class II aggregates disassemble and/or denature in the endosomes, and proper antigen presentation is impaired.

Clinical significance

Vaccine adjuvant

The Ii molecule—fused with aviral vectorto aconserved regionof theHepatitis C virus(HCV) genome—has been tested as anadjuvantfor aHCV vaccinein 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 futurevaccine 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. Seemilatuzumab.

Axial spondyloarthritis

Autoantibodiesagainst CD74 have been identified as promisingbiomarkersin the early diagnosis of theautoimmune diseasecalledaxial spondyloarthritis(non-radiographic axial spondyloarthritisandradiographic axial spondyloarthritis/Ankylosing spondylitis).

Interactions

CD74 receptorinteractswith the cytokineMacrophage 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, andHugh McDevittat Stanford.The nomenclature "Ii" comes from an Ix-based naming system (IforImmune) that predates the naming of theMajor Histocompatibility Complex.

See also

• Cluster of differentiation
• Milatuzumabthe 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.PMID16454711.
• 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.PMID1448172.S2CID4338656.
• 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.PMID2121367.S2CID19993336.
• 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.PMC2116304.PMID2391366.
• 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.PMID2507633.S2CID6755576.
• 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.PMC2189580.PMID3036998.
• 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.PMID3132422.S2CID2418453.
• 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.PMC323758.PMID3459184.
• 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.PMID3866610.
• 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.PMID6576808.
• 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.PMC557440.PMID6586420.
• 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.PMID6955026.S2CID9066996.
• 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.PMID6982931.S2CID42620266.
• 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.PMID7477400.S2CID4275956.
• 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.PMC2191624.PMID7519244.
• 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): 33–39.Bibcode:1993Natur.364...33B.doi:10.1038/364033a0.PMID8316295.S2CID4248668.
• 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.PMID8343954.S2CID10295196.
• 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.PMC47401.PMID8397411.

External links

• CD74+protein,+humanat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
• OverviewatDavidson College(student generated)
• School of CrystallographyThe Invariant Chain
• HumanCD74genome location andCD74gene details page in theUCSC Genome Browser.