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 CD74gene. The invariant chain (Abbreviated Ii) is a polypeptide involved in the formation and transport of MHC class II protein. The cell surface form of the invariant chain is known as CD74.
The nascent MHC class II protein in the rough ER binds a segment of the invariant chain (Ii; a trimer) in order to shape the peptide binding groove and prevent formation of a closed conformation.
The invariant chain also facilitates MHC class II's export from the ER 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. 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.
The stable MHC class-II with 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
^Baerlecken NT, Nothdorft S, Stummvoll GH, Sieper J, Rudwaleit M, Reuter S, Matthias T, Schmidt RE, Witte T (June 2014). "Autoantibodies against CD74 in spondyloarthritis". Annals of the Rheumatic Diseases. 73 (6): 1211–4. doi:10.1136/annrheumdis-2012-202208. PMID23687263.
Shan ZX, Lin QX, Deng CY, Tan HH, Kuang SJ, Xiao DZ, Zhu JN, Fu YH, Yu XY (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. PMID20034881.
^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. PMID20005040.
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. PMID3866610.
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. PMID6576808.
Kvist S, Wiman K, Claesson L, Peterson PA, Dobberstein B (May 1982). "Membrane insertion and oligomeric assembly of HLA-DR histocompatibility antigens". Cell. 29 (1): 61–9. doi:10.1016/0092-8674(82)90090-3. PMID6955026.
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. PMID6982931.
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. doi:10.1038/378457a0. PMID7477400.
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. doi:10.1038/364033a0. PMID8316295.
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. PMID8343954.