Furin-mediated protein processing in infectious diseases and cancer

Braun, Elisabeth; Sauter, Daniel

Retroviral glycoprotein trimers, such as those of human immunodeficiency, Rous sarcoma or murine leukaemia viruses, are proteolytically processed and activated in the producer cells (Figure 3a , left panel). In case of HIV-1, the gp160 precursor of the viral envelope protein (Env) is cleaved into gp120 and membrane-anchored gp41 that remain associated through noncovalent interactions. Cleavage occurs in intracellular compartments, before the assembly of virions at the plasma membrane. Notably, proteolytic processing of Env depends on correct N-linked glycosylation as aberrant carbohydrate side chains may result in subcellular mistrafficking or sequestration of Env. 49 Most likely, HIV-1 takes advantage of the redundancy of several proprotein convertases recognising the polybasic cleavage motif in Env. Furin, PCSK5, PCSK6 and PCSK7 have all been shown to cleave gp160 in cells, albeit with different efficiencies. 49 Notably, in vitro cleavage experiments using recombinant proteases did not always reflect cleavage efficiency in transfected cells and the relative contribution of individual PCSKs to HIV-1 maturation in vivo remains unclear. 49 Interestingly, HIV-1 Env harbours a second polybasic cleavage site, about eight amino acid residues upstream of the major one. Although cleavage at this site does not result in fusiogenic Env species, about 15% of all gp160 molecules are cleaved at this position, at least in case of the cellculture-adapted HIV-1 clone LAI. 50, 51 In some cases, gp160 escapes intracellular cleavage and may be incorporated as an unprocessed precursor into budding virions. Whether these Env molecules may be processed extracellularly by shed furin is unknown. In this context, it is noteworthy that membrane-bound plasmin has been shown to convert extracellular gp160 into gp120 and gp41. 52 However, it remains to be determined whether plasmin-mediated cleavage results in fully infectious HIV-1 particles.