Figure 1.

ER proteostasis pathways and secreted chaperones coordinate to regulate extracellular proteostasis. The integrity of the secreted proteome is regulated by the combined activity of proteostasis pathways localized to the ER and extracellular space. In the ER, quality control pathways partition secreted proteins between folding and degradation pathways to prevent secretion of nonnative and/or potentially aggregation-prone proteins to extracellular environments where they could aggregate into potentially toxic conformations. In the extracellular space, nonnative secreted proteins are bound by extracellular chaperones that prevent their aggregation and/or target these proteins to macrophages for endolysosomal degradation. Created with BioRender.com.