The role of suPAR and related proteins in kidney, heart diseases, and diabetes
Jochen Reiser, Salim S. Hayek, Sanja Sever
Jochen Reiser, Salim S. Hayek, Sanja Sever
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Review Cardiology Immunology Nephrology

The role of suPAR and related proteins in kidney, heart diseases, and diabetes

Abstract

The urokinase plasminogen activator receptor (uPAR) is a membrane-bound protein found on the surface of immune cells. Through the action of proteases, uPAR is cleaved to produce several circulating proteins in the bloodstream, including the soluble form suPAR and the fragments D1 and D2D3. Initially studied in the context of infectious diseases and cancer, recent research has revealed roles for suPAR and its related proteins as mediators linking innate immunity to the pathogenesis of kidney and cardiovascular diseases, as well as insulin-dependent diabetes. While these proteins have long been recognized as prognostic biomarkers, growing clinical, experimental, and genetic evidence highlights their active involvement in the onset and progression of these diverse conditions. This Review examines suPAR’s evolution from its discovery as a modulator of innate immunity to its current status as a key driver in chronic kidney and cardiovascular diseases. Furthermore, we explore the molecular mechanisms through which suPAR and D2D3 contribute to multiorgan damage, emphasizing emerging opportunities for therapeutic interventions across interconnected organ systems.

Authors

Jochen Reiser, Salim S. Hayek, Sanja Sever

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Figure 1

Posttranscriptional processing and proteolysis work together to produce multiple uPAR protein variants.

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Posttranscriptional processing and proteolysis work together to produce ...
(A) PLAUR, located on chromosome 19, produces multiple isoforms of uPAR through posttranscriptional processing. Isoform 1 is commonly known as uPAR. The nascent uPAR protein contains a short peptide at the N-terminus, which is crucial for targeting the protein to the secretory pathway. This sequence directs the ribosome-protein complex to the endoplasmic reticulum (ER), ensuring proper folding and posttranslational modifications, such as glycosylation and the addition of a glycosylphosphatidylinositol (GPI) anchor at the C-terminus. Once inside the ER, this signal sequence is cleaved by signal peptidase, leaving the mature protein to undergo further processing and localization at the plasma membrane. The glycosylation sites on asparagine (N) are indicated accordingly in the figure. Within the ER, the GPI transamidase recognizes a specific sequence at the protein’s C-terminus, cleaves the peptide bond, and transfers the GPI anchor to the glycine residue. Isoforms 1, 3, and 4 are GPI-anchored proteins, whereas isoform 2 lacks the GPI anchor and is directly secreted into circulation. (B) uPAR isoform 1 comprises three homologous domains: domain 1 (D1), D2, and D3. uPAR can be released from the plasma membrane into circulation through the action of multiple proteases. Proteolysis at the GPI anchor by phospholipase C (PLC), phospholipase D (PLD), or glycophosphodiesterase 3 (GDE3) generates circulating soluble uPAR (suPAR), consisting of D1, D2, and D3. Urokinase plasminogen activator (uPA), plasmin, and several matrix metalloproteinases (MMPs) predominantly cleave within the linker region between D1 and D2, releasing D1. These proteolytic events can indirectly facilitate the release of D2D3 or suPAR by exposing the GPI anchor to additional enzymes. Cooperative proteolysis by elastase and cathepsin G has been implicated in the formation of the D2D3 fragment. All structural models of UPAR_Human (UniProt accession number Q03405) were generated using AlphaFold version 2 (111).