An overworked ER sends out a distress signal called the unfolded protein response (UPR). The UPR helps the ER cope by increasing its folding capacity, and jettisoning those proteins that are hopelessly misfolded. The authors found that, under UPR-inducing conditions, most stressed cells had ER networks that are fivefold bigger than normal. But their electron micrographs also revealed many cells containing normal-sized ERs along with autophagosome-like structures packed selectively with ER stacks. The outer membranes of these structures were also derived from the ER, suggesting that the ER could be cannibalizing itself to return to normal size. Thus, says Walter, the ER can not only “counter-balance its expansion but also detoxify to improve the cell's chances of survival”.
UPR induction of many classical autophagy genes was crucial for cell survival during ER stress. But the sequestration and isolation of unhealthy ER may be more important than its eventual degradation, as cells that lacked a proper degradation system survived under UPR conditions.
It is not yet clear why damaged ER is toxic to cells, or how the ER is labeled for sequestration and packaged so selectively.