Heat shock protein A2 is a novel extracellular vesicle-associated protein

70-kDa Heat Shock Proteins (HSPA/HSP70) are chaperones playing a central role in the proteostasis control mechanisms. Their basal expression can be highly elevated as an adaptive response to environmental and pathophysiological stress conditions. HSPA2, one of poorly characterised chaperones of the HSPA/HSP70 family, has recently emerged as epithelial cells differentiation-related factor. It is also commonly expressed in cancer cells, where its functional significance remains unclear. Previously, we have found that proteotoxic stress provokes a decrease in HSPA2 levels in cancer cells. In the present study we found that proteasome inhibition-related loss of HSPA2 from cancer cells neither is related to a block in the gene transcription nor does it relate to increased autophagy-mediated disposals of the protein. Proteotoxic stress stimulated extracellular release of HSPA2 in extracellular vesicles (EVs). Interestingly, EVs containing HSPA2 are also released by non-stressed cancer and normal cells. In human urinary EVs levels of HSPA2 were correlated with the levels of TSG101, one of the main EVs markers. We conclude that HSPA2 may constitute basic components of EVs. Nevertheless, its specific role in EVs and cell-to-cell communication requires further investigation.

Automated summary

70-kDa Heat Shock Proteins (HSPA/HSP70) are important chaperones that regulate proteostasis. HSPA2, a poorly characterized member of the HSPA/HSP70 family, has been found to be associated with epithelial cell differentiation and expressed in cancer cells. Previous studies have shown that proteotoxic stress decreases HSPA2 levels in cancer cells. This study found that the loss of HSPA2 from cancer cells under proteasome inhibition is not due to blocked gene transcription or increased autophagy-mediated protein disposal. Instead, proteotoxic stress stimulates the release of HSPA2 in extracellular vesicles, which are also released by non-stressed cancer and normal cells. Levels of HSPA2 in human urinary extracellular vesicles are correlated with the levels of the extracellular vesicle marker TSG101. Further investigation is needed to determine the specific role of HSPA2 in extracellular vesicles and cell-to-cell communication.