HSP47: The new heat shock protein therapeutic target

Abstract

Heat shock proteins (HSPs) are part of a highly conserved genetic survival system originally discovered by Ferruccio Ritossa in 1962 (Ritossa, Riv Ist Sieroter Ital 37:79–108, 1962). Members of this family function as molecular chaperones that stabilize protein folding (De Maio, Shock 11:1–12, 1999). HSP47 is a molecular chaperone that is essential for collagen biosynthesis (Ishida et al., Mol Biol Cell 17:2346–2355, 2006; Matsuoka et al., Mol Biol Cell 15:4467–4475, 2004; Nagai et al., J Cell Biol 150:1499–1506, 2000). This chaperone is a potential therapeutic target, as it has been observed to be upregulated in collagen-producing cells in several fibrotic conditions (Taguchi et al., Acta Histochem Cytochem 44:35–41, 2011). The recent resolution of a HSP47 crystal structure has provided new insights into the chaperone’s mechanism of action (Widmer et al., Proc Natl Acad Sci U S A 109:13243–13247, 2012) with implications for future drug design. This review will summarize our current understanding of the biochemistry of HSP47-collagen interactions and the potential of HSP47 as a therapeutic target in fibrotic conditions. It will also discuss the current pharmacological inhibitors and the identification of new HSP47 small-molecule inhibitors.