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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.In contrast, under conditions of normal ER inheritance, ER protein aggregates can enter the daughter cell.

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

Inheritance of the ER and CPY* aggregates at different stages of the cell cycle.(A) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III, and unstressed cells (without Tm). (B) cER inheritance by different classes of WT cells expressing CPY*-mRFP and left untreated or subjected to additional ER stress with Tm (1 μg/ml, 2 hr). (C) Percentage of daughter cells containing CPY*-mRFP aggregates following incubation with or without Tm. (D) Percentage of daughter cells containing cER and CPY*-mRFP aggregates (yellow), cER but no CPY*-mRFP aggregates (gray), and neither cER nor CPY*-mRFP aggregates (blue) for each class of cells. (E) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III Tm-treated cells.DOI:http://dx.doi.org/10.7554/eLife.06970.005
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fig2s1: Inheritance of the ER and CPY* aggregates at different stages of the cell cycle.(A) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III, and unstressed cells (without Tm). (B) cER inheritance by different classes of WT cells expressing CPY*-mRFP and left untreated or subjected to additional ER stress with Tm (1 μg/ml, 2 hr). (C) Percentage of daughter cells containing CPY*-mRFP aggregates following incubation with or without Tm. (D) Percentage of daughter cells containing cER and CPY*-mRFP aggregates (yellow), cER but no CPY*-mRFP aggregates (gray), and neither cER nor CPY*-mRFP aggregates (blue) for each class of cells. (E) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III Tm-treated cells.DOI:http://dx.doi.org/10.7554/eLife.06970.005

Mentions: Because both CPY*-mRFP and GFP-CFTR form aggregates in the ER, we tested whether the difference in their transmission to daughter cells might lie in the different effects of the aggregates on ER function. Previous studies have reported that expression of CPY*, but not CFTR, induces the UPR (Chaudhuri et al., 1995; Zhang et al., 2001). Indeed, we found that induction of CPY*-mRFP resulted in the expression of a UPR reporter (UPRE-GFP, Figure 2A, lane 3), and this was further increased upon treatment of cells with the glycosylation inhibitor tunicamycin (Tm), a well-characterized ER stress inducer (Figure 2A, lane 4) (Cox et al., 1993; Mori et al., 1993). We also asked whether CPY* aggregates activate the ERSU pathway, which functions to ensure the inheritance of functional cER (Babour et al., 2010). We found that a majority of the class I daughter cells did not inherit the cER under the ER stress condition evoked by CPY*-mRFP expression, and cER inheritance was also diminished in class II and III cells, but to a much lesser extent (Figure 2B,C). Additionally, the magnitude of the cER inheritance block caused by CPY*-mRFP expression was less than that induced by Tm treatment (Figure 2C,E,F). Finally, we found that 63% of class I, 73% of class II, and 60% of class III daughter cells containing the cER also contained CPY* aggregates (Figure 2G; yellow vs gray bars). Taken together, these data indicate that for CPY*-mRFP-expressing cells, more than 65% of buds that inherited ER also contained at least one CPY* aggregate (Figure 2—figure supplement 1A). Conversely, 57% of buds without aggregates also lacked the ER (Figure 2G, light blue vs gray).10.7554/eLife.06970.004Figure 2.Differential inheritance of CPY* and CFTR aggregates and cER by daughter cells.


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

Piña FJ, Niwa M - Elife (2015)

Inheritance of the ER and CPY* aggregates at different stages of the cell cycle.(A) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III, and unstressed cells (without Tm). (B) cER inheritance by different classes of WT cells expressing CPY*-mRFP and left untreated or subjected to additional ER stress with Tm (1 μg/ml, 2 hr). (C) Percentage of daughter cells containing CPY*-mRFP aggregates following incubation with or without Tm. (D) Percentage of daughter cells containing cER and CPY*-mRFP aggregates (yellow), cER but no CPY*-mRFP aggregates (gray), and neither cER nor CPY*-mRFP aggregates (blue) for each class of cells. (E) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III Tm-treated cells.DOI:http://dx.doi.org/10.7554/eLife.06970.005
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Related In: Results  -  Collection

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Show All Figures
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fig2s1: Inheritance of the ER and CPY* aggregates at different stages of the cell cycle.(A) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III, and unstressed cells (without Tm). (B) cER inheritance by different classes of WT cells expressing CPY*-mRFP and left untreated or subjected to additional ER stress with Tm (1 μg/ml, 2 hr). (C) Percentage of daughter cells containing CPY*-mRFP aggregates following incubation with or without Tm. (D) Percentage of daughter cells containing cER and CPY*-mRFP aggregates (yellow), cER but no CPY*-mRFP aggregates (gray), and neither cER nor CPY*-mRFP aggregates (blue) for each class of cells. (E) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III Tm-treated cells.DOI:http://dx.doi.org/10.7554/eLife.06970.005
Mentions: Because both CPY*-mRFP and GFP-CFTR form aggregates in the ER, we tested whether the difference in their transmission to daughter cells might lie in the different effects of the aggregates on ER function. Previous studies have reported that expression of CPY*, but not CFTR, induces the UPR (Chaudhuri et al., 1995; Zhang et al., 2001). Indeed, we found that induction of CPY*-mRFP resulted in the expression of a UPR reporter (UPRE-GFP, Figure 2A, lane 3), and this was further increased upon treatment of cells with the glycosylation inhibitor tunicamycin (Tm), a well-characterized ER stress inducer (Figure 2A, lane 4) (Cox et al., 1993; Mori et al., 1993). We also asked whether CPY* aggregates activate the ERSU pathway, which functions to ensure the inheritance of functional cER (Babour et al., 2010). We found that a majority of the class I daughter cells did not inherit the cER under the ER stress condition evoked by CPY*-mRFP expression, and cER inheritance was also diminished in class II and III cells, but to a much lesser extent (Figure 2B,C). Additionally, the magnitude of the cER inheritance block caused by CPY*-mRFP expression was less than that induced by Tm treatment (Figure 2C,E,F). Finally, we found that 63% of class I, 73% of class II, and 60% of class III daughter cells containing the cER also contained CPY* aggregates (Figure 2G; yellow vs gray bars). Taken together, these data indicate that for CPY*-mRFP-expressing cells, more than 65% of buds that inherited ER also contained at least one CPY* aggregate (Figure 2—figure supplement 1A). Conversely, 57% of buds without aggregates also lacked the ER (Figure 2G, light blue vs gray).10.7554/eLife.06970.004Figure 2.Differential inheritance of CPY* and CFTR aggregates and cER by daughter cells.

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.In contrast, under conditions of normal ER inheritance, ER protein aggregates can enter the daughter cell.

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