Extracellular small heat shock proteins: exosomal biogenesis and function

Abstract

Small heat shock proteins (sHsps) belong to the family of heat shock proteins (Hsps): some are induced in response to multiple stressful events to protect the cells while others are constitutively expressed. Until now, it was believed that Hsps, including sHsps, are present inside the cells and perform intracellular functions. Interestingly, several groups recently reported the extracellular presence of Hsps, and sHsps have also been detected in sera/cerebrospinal fluids in various pathological conditions. Secretion into the extracellular milieu during many pathological conditions suggests additional or novel functions of sHsps in addition to their intracellular properties. Extracellular sHsps are implicated in cell-cell communication, activation of immune cells, and promoting anti-inflammatory and anti-platelet responses. Interestingly, exogenous administration of sHsps showed therapeutic effects in multiple disease models implying that extracellular sHsps are beneficial in pathological conditions. sHsps do not possess signal sequence and, hence, are not exported through the classical Endoplasmic reticulum-Golgi complex (ER-Golgi) secretory pathway. Further, export of sHsps is not inhibited by ER-Golgi secretory pathway inhibitors implying the involvement of a nonclassical secretory pathway in sHsp export. In lieu, lysoendosomal and exosomal pathways have been proposed for the export of sHsps. Heat shock protein 27 (Hsp27), αB-crystallin (αBC), and Hsp20 are shown to be exported by exosomes. Exosomes packaged with sHsps have beneficial effects in in vivo disease models. However, secretion mechanisms and therapeutic use of sHsps have not been elucidated in detail. Therefore, this review aimed at highlighting the current understanding of sHsps (Hsp27, αBC, and Hsp20) in the extracellular medium.

Keywords: Exosomes; Export; Plasma; Small heat shock proteins.

Fig. 1

Functions of extracellular heat shock protein 27 (eHsp27), αB-crystallin (eαBC), and Hsp20 (eHsp20). TLR: toll-like receptor; SR-A: scavenger receptor-A; VEGF: vascular endothelial growth factor; GM-CSF: granulocyte macrophage colony stimulating factor; ICAM-1: intercellular adhesion molecule1; MCP-1: monocyte chemoattractant protein-1; TNF-α: tumor necrosis factor; IL-6: interleukin-6; MSRA: macrophage scavenger receptor A; MARCO: macrophage scavenger receptor with collagenous structure; TNF-α: tumor necrosis factor; IL-2: interleukin-2; SOPT1: sodium oligopeptide transporter 1; VEGFR2: vascular endothelial growth factor receptor 2

Fig. 2

Hypothetical model for export of small heat shock proteins (sHsps) into the extracellular medium. sHsps may be part of the ESCRT-I complex and involved in the biogenesis of exosomes by directly interacting with Tsg101, an important component of the ESCRT-I machinery, and they might also act as a branch point to decide the fusion of MVBs with plasma membrane or lysosome