Limits...
The ER Stress Surveillance (ERSU) pathway regulates daughter cell ER protein aggregate inheritance.

Piña FJ, Niwa M - Elife (2015)

Bottom Line: Stress induced by cytoplasmic protein aggregates can have deleterious consequences for the cell, contributing to neurodegeneration and other diseases.By simultaneous visualization of both the ER itself and ER protein aggregates, we found that ER protein aggregates that induce ER stress are retained in the mother cell by activation of the ER Stress Surveillance (ERSU) pathway, which prevents inheritance of stressed ER.Thus, whereas cytoplasmic protein aggregates are retained in the mother cell to protect the functional capacity of daughter cells, the fate of ER protein aggregates is determined by whether or not they activate the ERSU pathway to impede transmission of the cortical ER during the cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Sciences, Section of Molecular Biology, Univeristy of California, San Diego, San Diego, United States.

ABSTRACT
Stress induced by cytoplasmic protein aggregates can have deleterious consequences for the cell, contributing to neurodegeneration and other diseases. Protein aggregates are also formed within the endoplasmic reticulum (ER), although the fate of ER protein aggregates, specifically during cell division, is not well understood. By simultaneous visualization of both the ER itself and ER protein aggregates, we found that ER protein aggregates that induce ER stress are retained in the mother cell by activation of the ER Stress Surveillance (ERSU) pathway, which prevents inheritance of stressed ER. In contrast, under conditions of normal ER inheritance, ER protein aggregates can enter the daughter cell. Thus, whereas cytoplasmic protein aggregates are retained in the mother cell to protect the functional capacity of daughter cells, the fate of ER protein aggregates is determined by whether or not they activate the ERSU pathway to impede transmission of the cortical ER during the cell cycle.

No MeSH data available.


Related in: MedlinePlus

Colocalization of cER and CPY* or CFTR aggregates.(A) Two representative fields of cells expressing the ER marker Hmg1-GFP and treated with galactose (Gal) for 2 hr to induce expression of CPY*-mRFP. (B) Representative field of Hmg1-GFP-expressing cells treated with galactose (Gal) and Tm for 2 hr to induce expression of CPY*-mRFP. (C) Representative field of cells expressing the ER marker DsRed-HDEL and treated with 100 μM copper (Cu) and Tm for 2 hr to induce expression of GFP-CFTR.DOI:http://dx.doi.org/10.7554/eLife.06970.007
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4555637&req=5

fig2s3: Colocalization of cER and CPY* or CFTR aggregates.(A) Two representative fields of cells expressing the ER marker Hmg1-GFP and treated with galactose (Gal) for 2 hr to induce expression of CPY*-mRFP. (B) Representative field of Hmg1-GFP-expressing cells treated with galactose (Gal) and Tm for 2 hr to induce expression of CPY*-mRFP. (C) Representative field of cells expressing the ER marker DsRed-HDEL and treated with 100 μM copper (Cu) and Tm for 2 hr to induce expression of GFP-CFTR.DOI:http://dx.doi.org/10.7554/eLife.06970.007

Mentions: Recently, it was reported that misfolded ER proteins were also retained in the mother cell when cells were exposed to relatively low levels of ER stress (0.5 μg/ml of Tm), as measured by Kar2sfGFP fluorescence recovery after photobleaching (FRAP) analysis (Clay et al., 2014). In our experiments, the moderate expression level of UPRE-GFP revealed that CPY*-mRFP aggregates induced a moderate level of ER stress (Figure 2A, lane 3) and also induced a mild block in ER inheritance compared with that induced by 0.5 μg/ml of Tm (compare Figure 2C,E,F, and Figure 2—figure supplement 3A). Based on the previous report, we anticipated that CPY*-mRFP expression alone (which induced low/medium levels of ER stress) should result in retention of CPY* aggregates in the mother cells. We observed, however, that CPY*-mRFP aggregates were distributed in both mother and daughter cells (Figure 2G, Figure 2—figure supplement 1A and Figure 2—figure supplement 3A). We also examined the effect of the compounded ER stress by treating CPY* aggregate-expressing cells with Tm (Figure 2—figure supplement 1B,E, and Figure 2—figure supplement 3B). As anticipated, the combined ER stresses further decreased ER inheritance by the daughter cells (Figure 2—figure supplement 1B). Notably, distribution of CPY* aggregates to the daughter cells was also further diminished in these cells (Figure 2—figure supplement 1C–E) and correlated with the reduced level of cER transmission (Figure 2—figure supplement 1B). Likewise, distribution of CFTR aggregates to the daughter cells was only diminished in cells in which ER inheritance was blocked by Tm treatment (Figure 2—figure supplement 2A,D, and Figure 2—figure supplement 3C). Collectively, these data therefore demonstrate that the magnitude of the ER inheritance block is affected by the level of ER stress, and that preferential retention of CPY* or CFTR aggregates in the mother cell is not an intrinsic property of the protein aggregates themselves, but rather, is dictated by ER inheritance.


The ER Stress Surveillance (ERSU) pathway regulates daughter cell ER protein aggregate inheritance.

Piña FJ, Niwa M - Elife (2015)

Colocalization of cER and CPY* or CFTR aggregates.(A) Two representative fields of cells expressing the ER marker Hmg1-GFP and treated with galactose (Gal) for 2 hr to induce expression of CPY*-mRFP. (B) Representative field of Hmg1-GFP-expressing cells treated with galactose (Gal) and Tm for 2 hr to induce expression of CPY*-mRFP. (C) Representative field of cells expressing the ER marker DsRed-HDEL and treated with 100 μM copper (Cu) and Tm for 2 hr to induce expression of GFP-CFTR.DOI:http://dx.doi.org/10.7554/eLife.06970.007
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555637&req=5

fig2s3: Colocalization of cER and CPY* or CFTR aggregates.(A) Two representative fields of cells expressing the ER marker Hmg1-GFP and treated with galactose (Gal) for 2 hr to induce expression of CPY*-mRFP. (B) Representative field of Hmg1-GFP-expressing cells treated with galactose (Gal) and Tm for 2 hr to induce expression of CPY*-mRFP. (C) Representative field of cells expressing the ER marker DsRed-HDEL and treated with 100 μM copper (Cu) and Tm for 2 hr to induce expression of GFP-CFTR.DOI:http://dx.doi.org/10.7554/eLife.06970.007
Mentions: Recently, it was reported that misfolded ER proteins were also retained in the mother cell when cells were exposed to relatively low levels of ER stress (0.5 μg/ml of Tm), as measured by Kar2sfGFP fluorescence recovery after photobleaching (FRAP) analysis (Clay et al., 2014). In our experiments, the moderate expression level of UPRE-GFP revealed that CPY*-mRFP aggregates induced a moderate level of ER stress (Figure 2A, lane 3) and also induced a mild block in ER inheritance compared with that induced by 0.5 μg/ml of Tm (compare Figure 2C,E,F, and Figure 2—figure supplement 3A). Based on the previous report, we anticipated that CPY*-mRFP expression alone (which induced low/medium levels of ER stress) should result in retention of CPY* aggregates in the mother cells. We observed, however, that CPY*-mRFP aggregates were distributed in both mother and daughter cells (Figure 2G, Figure 2—figure supplement 1A and Figure 2—figure supplement 3A). We also examined the effect of the compounded ER stress by treating CPY* aggregate-expressing cells with Tm (Figure 2—figure supplement 1B,E, and Figure 2—figure supplement 3B). As anticipated, the combined ER stresses further decreased ER inheritance by the daughter cells (Figure 2—figure supplement 1B). Notably, distribution of CPY* aggregates to the daughter cells was also further diminished in these cells (Figure 2—figure supplement 1C–E) and correlated with the reduced level of cER transmission (Figure 2—figure supplement 1B). Likewise, distribution of CFTR aggregates to the daughter cells was only diminished in cells in which ER inheritance was blocked by Tm treatment (Figure 2—figure supplement 2A,D, and Figure 2—figure supplement 3C). Collectively, these data therefore demonstrate that the magnitude of the ER inheritance block is affected by the level of ER stress, and that preferential retention of CPY* or CFTR aggregates in the mother cell is not an intrinsic property of the protein aggregates themselves, but rather, is dictated by ER inheritance.

Bottom Line: Stress induced by cytoplasmic protein aggregates can have deleterious consequences for the cell, contributing to neurodegeneration and other diseases.By simultaneous visualization of both the ER itself and ER protein aggregates, we found that ER protein aggregates that induce ER stress are retained in the mother cell by activation of the ER Stress Surveillance (ERSU) pathway, which prevents inheritance of stressed ER.Thus, whereas cytoplasmic protein aggregates are retained in the mother cell to protect the functional capacity of daughter cells, the fate of ER protein aggregates is determined by whether or not they activate the ERSU pathway to impede transmission of the cortical ER during the cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Sciences, Section of Molecular Biology, Univeristy of California, San Diego, San Diego, United States.

ABSTRACT
Stress induced by cytoplasmic protein aggregates can have deleterious consequences for the cell, contributing to neurodegeneration and other diseases. Protein aggregates are also formed within the endoplasmic reticulum (ER), although the fate of ER protein aggregates, specifically during cell division, is not well understood. By simultaneous visualization of both the ER itself and ER protein aggregates, we found that ER protein aggregates that induce ER stress are retained in the mother cell by activation of the ER Stress Surveillance (ERSU) pathway, which prevents inheritance of stressed ER. In contrast, under conditions of normal ER inheritance, ER protein aggregates can enter the daughter cell. Thus, whereas cytoplasmic protein aggregates are retained in the mother cell to protect the functional capacity of daughter cells, the fate of ER protein aggregates is determined by whether or not they activate the ERSU pathway to impede transmission of the cortical ER during the cell cycle.

No MeSH data available.


Related in: MedlinePlus