Identifying new molecular players in extracellular proteostasis

Proteostasis refers to a delicately tuned balance between the processes of protein synthesis, folding, localization, and the degradation of proteins found inside and outside cells. Our understanding of extracellular proteostasis is rather limited and largely restricted to knowledge of 11 currently established extracellular chaperones (ECs). This review will briefly outline what is known of the established ECs, before moving on to discuss experimental strategies used to identify new members of this growing family, and an examination of a group of putative new ECs identified using one of these approaches. An observation that emerges from an analysis of the expanding number of ECs is that all of these proteins are multifunctional. Strikingly, the armory of activities each possess uniquely suit them as a group to act together at sites of tissue damage, infection, and inflammation to restore homeostasis. Lastly, we highlight outstanding questions to guide future research in this field.