Hsp47 (Serpin H1) is a procollagen-specific molecular chaperone residing in the endoplasmic reticulum 22. Hsp47 serves as a critical regulator in intracellular processing during the assembly of triple-helical procollagen molecules 2, 3. Hsp47 is a clade H member of the SERPIN superfamily of proteinase inhibitors, but devoid of all inhibitory function. Hsp47 was originally characterized as a 47 kDa collagen-binding protein in chicken embryos whose expression is up-regulated upon heat shock 15. Hsp47 bears an N-terminal signal sequence, two N-glycosylation sites as well as a C-terminal ER-retention signal, RDEL 28, 29. Removal of the RDEL signal leads to rapid secretion out of cells as the modified molecule is no longer retained in the ER 26. There is a wealth of evidence illustrating that Hsp47 expression is highly tissue- and cell-specific, found predominantly in all collagen-producing cells, and constitutive expression levels coincide with collagen levels in the corresponding cell. Consequently, an up-regulated expression of Hsp47 is observed in a variety of fibrotic diseases including lung fibrosis and those affecting other organs 13, 150-155.
Hsp47 temporarily binds to triple-helical procollagen in the ER and is released subsequently in the cis-Golgi or the ER-Golgi intermediate compartment (ERGIC) under low pH 156. Apo-(unbound-) Hsp47 returns to the ER and is released into the ER lumen; this retrograde transport is mediated by an interaction of the C-terminal RDEL motif in Hsp47 with the KDEL receptor that cycles between the Golgi and ER 26. Beside its location to the ER, cis-Golgi and ERGIC 5, Hsp47 can be found in membrane rafts 6, the extracellular matrix (ECM) 11, on the surface of several cell types including activated human platelets 7-10 as well as in the serum of healthy and diseased human individuals 12-14. However, the molecular nature of the Hsp47 release is still unclear as heat shock proteins in general lack the consensus signal for secretion. Consequently, Hsp47 cannot be released from cells by the conventional secretory pathways. The mechanisms underlying its export may involve a number of non-canonical pathways including secretory lysosomes, microvesicles such as ecto- or exosomes, release in free form as well as necrotic mechanisms resulting in a passive leakage out of cells (reviewed by Calderwood et al., 2016) 157.