Hsp47 as a collagen-specific molecular chaperone

Heat shock protein (HSP) 47 is a 47 kDa collagen-binding glycoprotein localized in the endoplasmic reticulum (ER). It belongs to the serpin family and contains a serpin loop, although it does not have serine protease inhibitory activity. The induction of Hsp47 by heat shock is regulated by a heat shock element in its promoter region, while the constitutive and tissue-specific expression of Hsp47 correlates with that of collagen and is regulated via enhancer elements located in the promoter and intron regions. Hsp47 transiently binds to procollagen in the ER and dissociates in the cis-Golgi or ER-Golgi intermediate compartment region (ERGIC). Gene ablation studies indicated that Hsp47 is essential for embryonic development and the maturation of several types of collagen. The requirement for Hsp47 in collagen maturation may reflect its ability to inhibit collagen aggregation by binding procollagen in the ER and facilitate triple helix formation. In Hsp47-deficient cells, misfolded procollagen aggregates in the ER are degraded by the autophagy-lysosome pathway but not through the ubiquitin proteasome pathway. Hsp47 may be a therapeutic target for collagen-related disorders such as fibrosis, which feature abnormal accumulations of collagen and increased expression of Hsp47. This is supported by mouse models of fibrosis in which knockdown of Hsp47 clearly decreased the accumulation of collagen in fibrotic tissues and prevented the promotion of fibrosis. On the other hand, mutations in Hsp47 cause collagen-related genetic diseases such as osteogenesis imperfecta. Thus, Hsp47 is an indispensible molecular chaperone specific for collagen that is important in several major human diseases.