LYSOSOMES REPOSITION DURING ER STRESS

To figure out what the main function of the RIDD pathway is in mammalian cells, we investigated a particular target, encoding the protein Biogenesis of lysosome-related organelles 1 subunit 1 (Blos1). Blos1 is the best RIDD target! It is degraded robustly in a variety of types of mammalian cells in response to a variety of types of ER stress. Previous work showed that the protein Blos1 is part of complex that regulates trafficking of lysosomes toward the periphery of the cell. By looking at lysosomes during ER stress, we found that degradation of the Blos1 mRNA by the RIDD pathway leads to a dramatic repositioning of lysosomes and late endosomes to the microtubule organizing center in the center of the cell.

We can override Blos1 degradation by expressing a non-degradable version of the mRNA, containing a translationally silent point mutation in the cleavage site. This blocks the shifting of lysosomes and makes cells more sensitive to ER stress. The effect seems to be caused by the accumulation of protein aggregates, leading to lots of interesting questions about how lysosome positioning effects degradation of these (often toxic) aggregates. We are continuing to work on these questions, so stay tuned…

RELATED PUBLICATIONS

Bae D, Moore K, Mella J, Hayashi S, Hollien J. Degradation of Blos1 mRNA by IRE1 repositions lysosomes and protects cells from stress. Journal of Cell Biology. 2019. 218(4): 1118-1127.