FIGURE 2.

CSPα couples MAPS to eMI to promote lysosome homeostasis. In mammalian cells, CSPα triages cytosolic misfolded proteins by two different mechanisms: misfolding-associated protein secretion and eMI-mediated degradation. In both cases, an ER-associated deubiquitinase USP19 recruits and deubiquitinates misfolded substrates at the ER. For MAPS, CSPα and HSC70 guide the cargos to a peri-nuclear secretory compartment for unconventional protein secretion (CUPS). CD98hc is required for targeting of CSPα/substrate complexes to this compartment. After CSPα chaperones substrates to the lumen of CUPS, the encapsulated MAPS cargos and CSPα are secreted possibly by vesicular trafficking between the CUPS and plasma membrane (PM). For eMI, CSPα also escorts misfolded proteins into endolysosomes by an ESCRT-dependent mechanism. The resulting multivesicular bodies containing misfolded cargos can be degraded or secreted after the fusion of MVBs with lysosomes or plasma membrane. The box indicates how these two processes can be differentially regulated by different CSPα mutant proteins. The figure was created by BioRender.