Evidence that furin is an authentic transforming growth factor-beta 1-converting enzyme

Transforming growth factor (TGF)-beta1 plays an essential role in cell grow th and differentiation. It is also considered as a gatekeeper of immune hom eostasis with gene disruption leading to autoimmune and inflammatory diseas es. TGF-beta1 is produced as an inactive precursor polypeptide that can be efficiently secreted but correct proteolytic cleavage is an essential step for its activation. Assessment of the cleavage site has revealed a unique R -H-R-R sequence reminiscent of proprotein convertase (PC) recognition motif s and has previously demonstrated that this PC-like cleavage site is correc tly cleaved by furin, a member of the PC family, Here we report that among PC members, furin more closely satisfies the requirements needed to fulfill the role of a genuine TGF-beta1 convertase. Even though six members of the PC family have the ability to cleave TGF-beta1, ectopic expression of alph a (1)-antitrypsin Portland (alpha (1)-AT-PDX), a potent furin inhibitor, bl ocked 80% of TGF-beta1 processing mediated by endogenous enzymes as demonst rated in an in vitro digestion assay. Genetic complementation of a furin-de ficient LoVo cell line with the wild-type gene restores the production of m ature and bioactivable TGF-beta1, Moreover, both furin and TGF-beta are coo rdinately expressed and regulated in vitro and in vivo in the hematopoietic and immune system, an important tissue target. These results demonstrate f or the first time that furin is an authentic and adaptive TGF-beta1-convert ing enzyme whereas other members of the PC family might substitute or suppl ement furin activity. Our study advances our comprehension of the complexit y of the TGF-beta system and should facilitate the development of therapeut ically useful TGF-beta inhibitors.