UC Santa Barbara

ABSTRACT

A Physiological Unfolded Protein Response Impacts Progression Through the Cell CycleBy Soham Chowdhury

The cell cycle is a series of coordinated molecular steps that allow a progenitor cell to produce two daughter cells. During symmetrical cell division, a mother cell’s particular organelle makeup must also be inherited by the daughter cells. Multi-copy organelles such as mitochondria divide and are equally distributed between daughter cells. Single copy organelles such as the endoplasmic reticulum (ER) and the Golgi apparatus however must be first expanded, then fragmented, and finally partitioned to each daughter cell. Such organelle expansion requires the production of new membranes. Being that the ER is the site of endomembrane biosynthesis, we reasoned that ER expansion should precede and be necessary for mammalian cell division. The Unfolded Protein Response (UPR) is an evolutionarily conserved collection of signaling pathways that maintain ER health. Protein folding perturbations in the ER lumen as well disturbances of the ER membrane lipid bilayer trigger ER stress and activate the UPR. The UPR mitigates ER stress by increasing the biosynthetic and protein degradative capacities of the ER, including its physical expansion through endomembrane biogenesis. Here we show that as cells grow through interphase, their ER chaperone and foldase contents increase, as does the ER volume, indicating that ER expansion precedes cell division. Moreover, pharmacological inhibition of the UPR sensors IRE1 and ATF6 at steady-state delayed cell cycle progression. Furthermore, we found that the threshold for UPR activation is lower in the S/G2 stage of the cell cycle suggesting that ER expansion and increased ER protein-processing capacity is subsequent to genome duplication. Finally, our data indicate that IRE1 activity is dampened by the G2/M cell cycle checkpoint kinase PKMYT1 suggesting negative feedback control. Taken together, these findings suggest a physiological role for the UPR in coordinating the mammalian cell cycle