Furin-mediated protein processing in infectious diseases and cancer

Braun, Elisabeth; Sauter, Daniel

In 2013, Aerts and colleagues found that protease-activated receptor 1 (PAR1), a G-proteincoupled receptor, interferes with the expression of furin and furin-mediated processing of the human metapneumovirus F protein. 91 Follow-up experiments revealed that PAR1 harbours an R 41 XXXXR 46 motif that mediates interaction with several PCSKs. 92 In line with this, soluble PC5A/ PCSK5 and PCSK6 cleave PAR1 at R 46 ↓ and abrogate its ability to induce calcium signalling upon thrombin-mediated cleavage at the plasma membrane. Surprisingly, however, membranebound PCSKs such as furin fail to cleave PAR1 at this position. Instead, furin traps PAR1 in the trans-Golgi network and prevents its anterograde transport to the cell surface (Figure 4a ). At the same time, PAR1 also blocks the proteolytic activity of furin, inhibiting for example the maturation of HIV-1 Env. This inhibitory activity is not shared by its paralogue PAR2, which is efficiently cleaved by furin. 93 Notably, expression of PAR1 is induced in proinflammatory environments such as the brain of HIV-1 infected individuals suffering from HIV-associated neurocognitive disorders (HAND). 92 Thus, PAR1mediated furin inhibition may represent a mechanism of innate immunity limiting the spread of HIV-1 and potentially additional furindependent viral pathogens.