Extracellular chaperone networks and the export of J-domain proteins

Abstract

An extracellular network of molecular chaperones protects a diverse array of proteins that reside in or pass through extracellular spaces. Proteins in the extracellular milieu face numerous challenges that can lead to protein misfolding and aggregation. As a checkpoint for proteins that move between cells, extracellular chaperone networks are of growing clinical relevance. J-domain proteins (JDPs) are ubiquitous molecular chaperones that are known for their essential roles in a wide array of fundamental cellular processes through their regulation of heat shock protein 70s. As the largest molecular chaperone family, JDPs have long been recognized for their diverse functions within cells. Some JDPs are elegantly selective for their "client proteins," some do not discriminate among substrates and others act cooperatively on the same target. The realization that JDPs are exported through both classical and unconventional secretory pathways has fueled investigation into the roles that JDPs play in protein quality control and intercellular communication. The proposed functions of exported JDPs are diverse. Studies suggest that export of DnaJB11 enhances extracellular proteostasis, that intercellular movement of DnaJB1 or DnaJB6 enhances the proteostasis capacity in recipient cells, whereas the import of DnaJB8 increases resistance to chemotherapy in recipient cancer cells. In addition, the export of DnaJC5 and concurrent DnaJC5-dependent ejection of dysfunctional and aggregation-prone proteins are implicated in the prevention of neurodegeneration. This review provides a brief overview of the current understanding of the extracellular chaperone networks and outlines the first wave of studies describing the cellular export of JDPs.

Keywords: DnaJ; EVs; J-domain proteins; JDP; exosomes; extracellular chaperones; extracellular vesicles; misfolded proteins; molecular chaperones.

Figure 1

Secretion of JDPs.A, schematic cartoon of the structural similarities and differences between the subclasses of JDPs DnaJA, DnaJB, and DnaJC. Exported JDPs are indicated. The defining domain architecture of the subclasses is shown. The DnaJCs have the greatest diversity in size and architecture, as the J domain may be present anywhere in the structure of the protein. Adapted from Ref. (8). B, schematic overview of the secretory pathways for JDPs in mammalian cells. A diverse array of proteins and molecular chaperones transverse the extracellular space. In the classical secretory pathway, JDPs containing signal sequences are translocated into the endoplasmic reticulum, pass through the Golgi complex, and are released from the plasma membrane. In the unconventional secretory pathway, JDPs are exported in extracellular vesicles (EVs). EVs that are heterogeneous in both size and content are produced through the endosomal pathway by fusion of multivesicular bodies (MVBs) with the plasma membrane (exosomes) as well as by the outward blebbing and pinching of the plasma membrane. Following secretion in the extracellular space, EV and nonvesicular JDPs are taken up by recipient cells through multiple mechanisms. C, cysteine-rich region; CCC, cysteine string region; CTD-I and CTD-II, C-terminal domains involved in substrate binding; DD, dimerization motif; G/F, glycine/phenylalanine linker; J, J-domain; JDP, J-domain protein; SS, signal sequence; S/T, serine–threonine–rich region; ZFLR, zinc finger–like region.