ERphagy In Yeast:

ERphagy and ERAD:

Selective ERphagy is tightly linked to ER stress and in particular the unfolded protein response (UPR)\cite{Yorimitsu2006,Kruse2006,Kamimoto2006,Kouroku2007}. ER stress causes a significant ER expansion, and is also associated with an increase in autophagosome numbers. While this connection was made in the early 1970’s only recently has the mechanism behind these observations been studied. UPR is initiated by an overabundance of misfolded proteins in the ER lumen. This occurs when cellular demand for membrane/secreted proteins exceeds the ER’s ability to facilitate protein folding. Bernales et al. asked what changes in ER morphology happened upon UPR induction in yeast by dithiothreitol\cite{Bernales2007}. Using thin section electron microcopy, they observed a large expansion of ER volume and a change in morphology biasing the ER towards large sheet domains. Upon further examination, Bernales et al. noted that in a subset of cells UPR resulted in a marked increase in double membrane autophagosome like structures packed with membrane cisternae. They hypothesized that these were autophagosomes which had specifically internalized ER membrane in response to UPR. Bernales et al. went on to show that these structures did indeed contain ER membrane and that the formation of these structures was dependent on autophagosomal machinery. When the autophagosomal machinery was knocked out the cells were no longer able to tolerate dithiothreitol induced UPR suggesting that ERphagy is an essential component of UPR. Interestingly, the degradation of the membrane contents seemed to be unnecessary for the survival of cells. As long as the ER membrane was packed in autophagosomes the cells were able to tolerate the dithiothreitol induced UPR.

ERphagy and ER Stress: 

ERphagy has also been connected with the clearance of large protein aggregates in the ER. Kruse et al. asked what cellular processes were implicated in a liver disease associated with a mutant aggregate prone (AP) fibrinogen\cite{Kruse2006}. They showed that upon high expression of AP fibrinogen proteasomal degradation was no longer sufficient to clear aggregates. In these high expression conditions ERphagy was required to clear the AP fibrinogen. This implicates ERphagy not only in the liver disease but also basic protein quality control and ER homeostasis.
Further investigation of the role of ERphagy in maintaining ER homeostasis by Schuck et al. highlighted a role for ERphagy in basic ER stress response\cite{Schuck2014}. They showed that, tunicamycin induced ER stress is associated with an increase in not only ER size but also abnormal ER structures they term ER whorls. They observed by electron microscopy that ER whorls were internalized directly by the vacuole. Through knockout they discovered that this form of microautophagy of the ER is not dependent on any of the canonical autophagy genes (atg1, atg6, atg7, atg8, atg14, atg16). Linking Pho8D60, a marker of vacuole internalization, to ER and cytoplasmic proteins Schuck et al. were able to demonstrate that ER stress results in the selective increase in ERphagy and not a general increase in autophagy. This indicates that ER stress was able to activate an alternative ER specific microautophagy and not other forms of generally autophagy. The signaling cascade involved in the recognition of ER whorls, their separation from the rest of the ER membrane, binding to the vacuole, and internalization has not yet been elucidated.