HLA class II-associated invariant chain (CD74) (CD74)

CD74, also known as the HLA class II-associated invariant chain (Ii), is a non-polymorphic type II transmembrane glycoprotein essential for the MHC class II antigen presentation pathway [1, 4]. It functions as a molecular chaperone, stabilizing MHC class II alpha-beta heterodimers in the endoplasmic reticulum and blocking the peptide-binding groove with its Class II-associated invariant chain peptide (CLIP) region to prevent premature loading of endogenous peptides [4]. During transport through the endocytic pathway, CD74 is proteolytically processed, leaving the CLIP fragment in the groove until it is catalyzed for exchange with exogenous antigenic peptides by HLA-DM [1]. Beyond its chaperone role, CD74 acts as a high-affinity receptor for Macrophage Migration Inhibitory Factor (MIF), activating survival pathways such as NF-kappaB and MAPK/ERK, which are often hijacked in malignancies [2]. CD74 is highly expressed in B-cell lineages and various cancers, including multiple myeloma and non-Hodgkin lymphoma, making it a validated target for monoclonal antibodies and antibody-drug conjugates (ADCs) like milatuzumab [3]. Therapeutic targeting of CD74 or the CLIP/MHC II complex offers a dual approach: direct induction of apoptosis in tumor cells and modulation of the immune microenvironment [3, 4]. Sources: [1] UniProt Consortium. CD74 - HLA class II antigen-associated invariant chain. UniProtKB - P04233. [2] Beswick, E. J., et al. (2009). CD74: a receptor for macrophage migration inhibitory factor with a role in cancer. Expert Opinion on Therapeutic Targets. [3] Stein, R., et al. (2007). CD74: a new candidate target for the immunotherapy of B-cell neoplasms. Clinical Cancer Research. [4] Roche, P. A., & Furuta, K. (2015). The ins and outs of MHC class II-mediated antigen processing and presentation. Nature Reviews Immunology.

Other names

CLIPClass II-associated invariant chain peptideInvariant chainIip33p35p41p43HLA-DR-associated invariant chain

Monoclonal antibodies target CD74 on the cell surface, leading to rapid internalization and induction of apoptosis or delivery of cytotoxic payloads in the case of antibody-drug conjugates. It also functions by blocking the binding of Macrophage Migration Inhibitory Factor (MIF) to CD74, thereby inhibiting pro-survival signaling pathways such as MAPK/ERK and NF-kappaB.