Endosome maturation during ER stress relies on the ubiquitin-binding domain of histone deacetylase 6.

Histone deacetylase 6 (HDAC6) helps cells manage misfolded proteins by transporting ubiquitin (UB)-associated structures toward the microtubule organizing center, where they can be sequestered and degraded by lysosomes. Here, we show that when cells are subjected to acute protein-folding stress in the endoplasmic reticulum (ER), HDAC6 depletion results in the appearance of enlarged endosomes that are highly decorated with UB and colocalize with both early and late endosome markers. The C-terminal UB-binding domain and adjacent disordered regions of HDAC6 are necessary and sufficient to rescue this endosomal phenotype in cells lacking endogenous HDAC6. HDAC6 deficiency does not appear to prevent the recruitment of endosomal sorting complexes required for transport (ESCRT), which coordinate endosome maturation. However, overexpression of HDAC6 can reverse endosome phenotypes associated with the depletion of the early ESCRT factor HRS. We speculate that HDAC6 facilitates the packaging and processing of endosomal cargo when the endomembrane system is under stress.