CD74 MHC class II associated invariant chain (Ii), class II specific chaperone
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 2 glycoprotein
B Cell
T Cell
Epithelial Cell
Endothelial Cell
Macrophage
Antigen presenting cell
MHC class II cell
33 / 33
35 / 35
41 / 41
43 / 43
45 / 45

Expression
CD74 is mostly expressed intracellularly on MHC class II-positive cells.  There is moderate surface expression on B cells, other antigen presenting cells and weak surface expression on monocytes.  CD74 is also expressed on a subset of activated T cells, B cells, macrophages and activated endothelial and epithelial cells.



Structure
MOLECULAR FAMILY NAME:

CD74 is a single-pass type-2 glycoprotein.  It consists of 9 exons and 4 major isoforms that are generated by variable splicing and alternative usuage of two in phase initiation condons.  CD74 isoforms Ii33 and Ii35 are both encoded by 8 exons but differ by 16 N-terminal aa due to alternative translation initiation.  CD74 isoform Ii 33 contains an 160 aa luminal extracellular region, a 26 aa transmembrane region and 33 aa cytoplasmic domain of 30 aa.   CD74 isoform Ii 35 contains an endoplasmic reticulum (ER) retention signal and a sorting close to the N-terminus.  A stretch formed by residues 81-104 is the class II binding site and is called class II associated invariant chain peptide, CLIP.   Residues 91-99 of CLIP occupy the groove of class II heterodimers during intracellular transport.  A stretch formed by residues 163 and 183 is the site where newly formed  CD74 Li molecules trimerizes.  An addition of exon 6b, yields isoform Ii41 and Ii43 which results in 6 cysteine-rich stretch of 64 aa near C-terminus which has sequence similarity to thyroglobulin type 1 repeats centered around the Cys-Trp-Cys-Val motif.  CD74 contains 2 or 4 N-glycosylation sites as well as 2 O-glycosylation sites and minor subfractions which are palmitylated, sulfated, phosphorylated or contain glycosaminoglycan side chains.    

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Various 33 kDa, 35 kDa, 41 kDa, 43 kDa, 45 kDa Isoforms


POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields several different isoforms.

POST-TRANSLATIONAL MODIFICATION

During Golgi passage, Ii polypeptides can be N- and O-glycosylated.  A proteoglycan form of Ii can arise through chondroitin sulfate (CS) linkage to serin-201. 


Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD74
Molecule Comment
HLA-DR heterodimers
CD44 Single observation not yet been confirmed by other labs




Function
The primary function of CD74 is the intracellular sorting of the MHC class II molecules.  CD74 homotrimers associate in the ER with 3 MHC class II ab dimers and this prevents the binding of endogenous peptides to class II molecules.  The N-terminal cytoplasmic domain of CD74 contains targeting motifs which leads to its retention in the ER, or to targeting of class II ab dimers into the endosomal-lysosomal pathway via the Golgi. Subsequent proteolytic degradation of CD74 leaves a small fragment CLIP bound to class II ab dimers in the peptide-binding groove.  The interaction of class II ab/CLIP complexes with HLA-DM, a class II-related ab dimer, in a specialized compartment releases the CLIP and allows the class II molecules to bind peptides derived from exogenous proteins.  CD74-deficient mice have reduced levels of MHC class II at the cell surface and these molecules lack the compact conformation indicative of bound peptide.  Consequently these mice have reduced numbers of peripheral CD4+ T cells and their antigen-presenting cells present protein antigens very poorly.  CD74 is required for normal positive selection of CD4+ T cells.  In vitro, chondroitin sulphated CD74 (IiCD) can act as an accessory molecule enhancing activation of primary T cell responses through the interaction with CD44 on CD44+ T cells.  CD74 may be required for endocytosis of MHC class II molecules as cell surface MHC class II-CD74 complexes are rapidly internalized to endosomes.  Knockout mice have deficient MHC class II assembly and transport, decreased surface expression of class II molecules, altered antigen presentation, and inefficient positve selection of CD4+ T cells.  Those CD4+ cells that do mature display aberrant peripheral activiation.  The cell surface form of CD74 binds macrophage migration inhibitory factor (MIF) with high affinity and this interaction leads to activation of the extracellular signal-regulated cascade (ERK)-1/2 MAP kinase signal cascade, PGE2 production and cell proliferation.  In certain cell types CD44 recruitment into the CD74-MIF complex may be necessary for MIF signal transduction can occur.  

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD74 IN INTACT ANIMAL

CD74 is useful in the study of antigen presentation and processing and the analysis of subcellular compartments.  CD74 is involved in phenotyping of leukemias and lymphomas.  It is a potential target for treatment of malignancies and immunologic diseases due to its restricted expression in normal tissues and rapid internalization.

Comments
Expression of CD74 and the MHC class II a and b chains is co-regulated and induced by IFNg.  Coordinate expression of these 3 genes may be directed by a segment of sequence homology at the 5' region of each gene.

MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD74
Molecule Comment
NF-kB The promoter region of the Ii gene has 2 NF-kB binding sites

Expression of Ii and MHC class II polypeptides are co-regulated and expression is induced by IFN-g, IL-4 and by TNFa .

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD74
Molecule Comment
Cathepsin S Within the MHC class II loading compartment,
then HLA-DM removes CLIP


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 972P04233
MouseA02244P04441X00496
RatS02182P10247X14254
Antibodies
LN2   View Reactivity
M-B741   View Reactivity

Revised June 25, 2008


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