Roles of the endoplasmic reticulum–resident, collagen-specific molecular chaperone Hsp47 in vertebrate cells and human disease

Abstract

Heat shock protein 47 (Hsp47) is an endoplasmic reticulum (ER)-resident molecular chaperone essential for correct folding of procollagen in mammalian cells. In this Review, we discuss the role and function of Hsp47 in vertebrate cells and its role in connective tissue disorders. Hsp47 binds to collagenous (Gly-Xaa-Arg) repeats within triple-helical procollagen in the ER and can prevent its local unfolding or aggregate formation, resulting in accelerating triple-helix formation of procollagen. Hsp47 pH-dependently dissociates from procollagen in the cis-Golgi or ER-Golgi intermediate compartment and is then transported back to the ER. Although Hsp47 belongs to the serine protease inhibitor (serpin) superfamily, it does not possess serine protease inhibitory activity. Whereas general molecular chaperones such as Hsp70 and Hsp90 exhibit broad substrate specificity, Hsp47 has narrower specificity mainly for procollagens. However, other Hsp47-interacting proteins have been recently reported, suggesting a much broader role for Hsp47 in the cell that warrants further investigation. Other ER-resident stress proteins, such as binding immunoglobulin protein (BiP), are induced by ER stress, whereas Hsp47 is induced only by heat shock. Constitutive expression of Hsp47 is always correlated with expression of various collagen types, and disruption of the Hsp47 gene in mice causes embryonic lethality due to impaired basement membrane and collagen fibril formation. Increased Hsp47 expression is associated with collagen-related disorders such as fibrosis, characterized by abnormal collagen accumulation, highlighting Hsp47's potential as a clinically relevant therapeutic target. cro REVIEWS

Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice

“…The role of TNC in promoting pulmonary fibrosis is also supported by attenuation of bleomycin-induced fibrosis in Tnc-deficient mice 52 . In addition, we found SER-PINH1, a chaperone involved in collagen maturation 53 , among the commonly upregulated matrisome proteins. SERPINH1, has been shown to be increased in AT2 cells and myofibroblasts of IPF patients, where it induces overexpression of type I procollagen contributing to the general tissue disorganization 54 .…”

Ascorbic Acid Promotes Procollagen C‐Proteinase Enhancer 1 Expression, Secretion, and Cell Membrane Localization

“…PCPE‐1 may also function as a chaperone required for procollagen stability and/or transport. Similar functions have been ascribed to Hsp47, a collagen‐specific chaperone that in addition to stabilization of the collagen triple helix has been shown to mediate interaction of procollagens with transmembrane protein transport and Golgi organization 1 (TANGO1), a protein involved in loading procollagen molecules into special coat protein complex II (COPII) vesicles for transport (Ishikawa et al, ; Maiers et al, ; Raote et al, ; Ito and Nagata, ). Dependence of PCPE‐1 secretion and membrane localization on Asc may reflect such an association between PCPE‐1 and procollagen secretion.…”

Presence of heat shock protein 47-positive fibroblasts in cancer stroma is associated with increased risk of postoperative recurrence in patients with lung cancer

“…Therefore, HSP47 is strongly associated with collagen-related brotic diseases, including liver, heart, kidney and pulmonary brosis. [2] We have reported that HSP47 expression is upregulated and associated with progression of pulmonary brosis and pulmonary brotic disorders using animal models of the same in humans. [3][4][5][6][7] HSP47 has also been reported to be associated with several types of cancers, including cervical, breast, pancreatic, gastric, and colon cancer.…”