title: SerpinB6 is an inhibitor of kallikrein-8 in keratinocytes.
abstract: SerpinB6 (Proteinase inhibitor 6/PI-6) is an intracellular serpin produced by leukocytes, platelets, endothelial cells, keratinocytes and other epithelial cells. It is a potent cathepsin G inhibitor thought to protect monocytes, neutrophils and bystander cells from ectopic cathepsin G during inflammation. Here we show that serpinB6 also inhibits the human serine protease kallikrein-8 (hK8) and that in human and mouse skin, serpinB6 and kallikrein-8 co-localize in differentiated keratinocytes. SerpinB6 inhibits hK8 with an association rate constant (kass) of 1.8 +/- 0.2 x 10(5) M(-1)s(-1) compared to 3.4 +/- 0.2 x 10(6) M(-1) s(-1) for the interaction between the mouse orthologue of serpinB6 (SPI3/serpinb6a) and mouse kallikrein-8 (mK8). Molecular modelling suggested that the lower efficiency of the serpinB6/hK8 interaction is partly due to the bulkier P2 methionine residue of serpinB6 compared to the smaller P2 valine in SPI3. Taken together, these results suggest that serpinB6 is a physiologically relevant inhibitor of hK8 in skin. We postulate that serpinB6 protects the intracellular compartment of keratinocytes from ectopic hK8.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia. fscott@burnham.org
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Scott
authors.forename: Jiuru
authors.initials: J
authors.lastname: Sun
authors.forename: James C
authors.initials: JC
authors.lastname: Whisstock
authors.forename: Keiko
authors.initials: K
authors.lastname: Kato
authors.forename: Phillip I
authors.initials: PI
authors.lastname: Bird
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D007424:Intracellular Fluid / Q000201:enzymology / Q000378:metabolism; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015843:Serpins / Q000737:chemistry / Q000502:physiology*
chemical_list: D015843:Serpins; C094472:serpin B6; C094799:KLK8 protein, human; D007610:Kallikreins