CD74 and Proteases: Impact of Location on Immune and Cellular Functions

Proteases represent a diverse family of enzymes that catalyze the hydrolysis of peptide bonds, modulating numerous biological processes. Among their substrates, CD74-also known as the invariant chain-has received increased research attention due to its multifunctional roles in both innate and adaptive immunity. This review provides an overview of current knowledge on protease-mediated interactions with CD74. The protein was originally identified as a chaperone for major histocompatibility complex class II (MHC-II) molecules. Proteolytic cleavage of CD74, most notably by cathepsin S, is essential for the release of MHC-II and the initiation of antigen presentation. However, CD74 has since emerged as a central regulator of processes extending well beyond antigen presentation. More recent findings reveal that CD74, acting as a receptor of macrophage migration inhibitory factor, also participates in signaling pathways in non-immune cells, independent of its classical chaperone function. Proteolytic processing of CD74 can trigger signaling cascades that modulate gene expression, underscoring its multifunctionality. Dysregulation of CD74 cleavage and its interaction with proteases has been linked to diverse pathological conditions, including cancer and autoimmune diseases, where aberrant protease activity disrupts CD74 function and promotes disease progression.