Abstract
CD74 (invariant MHC class II) regulates protein trafficking and is a receptor for macrophage migration inhibitory factor (MIF) and d-dopachrome tautomerase (d-DT/MIF-2). CD74 expression is increased in tubular cells and/or glomerular podocytes and parietal cells in human metabolic nephropathies, polycystic kidney disease, graft rejection and kidney cancer and in experimental diabetic nephropathy and glomerulonephritis. Stressors like abnormal metabolite (glucose, lyso-Gb3) levels and inflammatory cytokines increase kidney cell CD74. MIF activates CD74 to increase inflammatory cytokines in podocytes and tubular cells and proliferation in glomerular parietal epithelial cells and cyst cells. MIF overexpression promotes while MIF targeting protects from experimental glomerular injury and kidney cysts, and interference with MIF/CD74 signaling or CD74 deficiency protected from crescentic glomerulonephritis. However, CD74 may protect from interstitial kidney fibrosis. Furthermore, CD74 expression by stressed kidney cells raises questions about the kidney safety of cancer therapy strategies delivering lethal immunoconjugates to CD74-expressing cells. Thus, understanding CD74 biology in kidney cells is relevant for kidney therapeutics.
Highlights
Protein TraffickingCD74 interacts with MHC class I and II proteins, contributing to antigen presentation
The role of CD74 in kidney injury has barely been explored and the scarce information available is derived from CD74-deficient mice that may not recapitulate the findings of targeting CD74 de novo in an adult
Like migration inhibitory factor (MIF), CD74 may protect from experimental kidney interstitial fibrosis but promotes glomerular injury, while MIF promotes polycystic kidney disease
Summary
CD74 interacts with MHC class I and II proteins, contributing to antigen presentation. CD74 directs transport of MHC class II α and β chains from the endoplasmic reticulum (ER) or the cell surface to endosomes [6]. CD74 contributes to peptide editing in the MHC class II compartment. Proteases degrade CD74, releasing MHC class II molecules. Prevention of CD74 degradation promotes the cell surface localization of MHC II. Extracellular CD74/cathepsin L complexes are found in human kidneys [1, 7, 8]. CD74 associates with angiotensin II type I receptors (AT1), leading to AT1 proteasomal degradation [9]
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