CD74 is expressed on antigen-presenting cells and was initially demonstrated to function as an MHC class II chaperone []. It was originally described as the MHC class II-associated invariant chain and its binding to MHC II alpha and beta chains is crucial for the MHCII antigen presentation pathway. Besides chaperone function, it is also involved in the regulation of endosomal trafficking, cell migration and cellular signalling as surface receptor of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) []. Macrophage migration inhibitory factor binding to CD74 induces its intramembrane cleavage and the release of its cytosolic intracellular domain (CD74-ICD), which interacts with the transcription factors RUNX (Runt related transcription factor) and NF-kappaB and binds to proximal and distal regulatory sites enriched for genes involved in apoptosis, immune response, and cell migration. Recently, CD74 has been associated with tumor progression and metastasis [].
The CD74 antigen (also known as H-2 class II histocompatibility antigen gamma chain, MHC class II-associated invariant chain, Ia antigen-associated invariant chain, or Ii) plays a key role in MHC class II antigen processing: it stabilises peptide-free class II alpha/beta heterodimers in a nonameric (α-β-gamma)3 complex after their synthesis, and directs transport of the complex from the endoplasmic reticulum to compartments where peptide loading of class II takes place []. CD74/Ii is a single-pass type II membrane protein containing a thyroglobulin type-1 domain. The structure of the trimeric domain of the MHC class II-associated chaperonin and targeting protein Ii has been determined by NMR []. The molecule is cylindrical in shape and reveals conserved molecular surfaces that may mediate interactions between Ii and class II molecules [].
