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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

Colocalization of ER and CPY* or CFTR in slt2Δ cells.(A) Representative field of Hmg1-GFP-expressing slt2Δ cells treated with galactose (Gal) for 2 hr to induce expression of CPY*-mRFP. (B) Representative field of DsRed-HDEL-expressing cells treated with 100 μM copper (Cu) for 2 hr to induce expression of GFP-CFTR. (C) Representative field of DsRed-HDEL-expressing cells treated with 100 μM copper (Cu) and Tm for 2 hr to induce expression of GFP-CFTR. Note that slt2Δ cells do not exhibit a block in ER inheritance under ER stress. (D) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III cells.DOI:http://dx.doi.org/10.7554/eLife.06970.009
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fig3s1: Colocalization of ER and CPY* or CFTR in slt2Δ cells.(A) Representative field of Hmg1-GFP-expressing slt2Δ cells treated with galactose (Gal) for 2 hr to induce expression of CPY*-mRFP. (B) Representative field of DsRed-HDEL-expressing cells treated with 100 μM copper (Cu) for 2 hr to induce expression of GFP-CFTR. (C) Representative field of DsRed-HDEL-expressing cells treated with 100 μM copper (Cu) and Tm for 2 hr to induce expression of GFP-CFTR. Note that slt2Δ cells do not exhibit a block in ER inheritance under ER stress. (D) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III cells.DOI:http://dx.doi.org/10.7554/eLife.06970.009

Mentions: We reasoned that if the ERSU pathway-dependent ER inheritance regulates the distribution of protein aggregates to the daughter cell, then cells lacking the ERSU pathway should also show diminished retention of protein aggregates in the mother cell. To test this, we examined the distribution of CFTR and CPY* aggregates in slt2Δ cells, which are incapable of blocking ER inheritance in response to ER stress. We reported previously that Tm (1 μg/ml) treatment does not block cER inheritance in slt2Δ cells (Babour et al., 2010) and this was also observed in slt2Δ cells when ER stress was induced by CPY* aggregate expression (Figure 3A +Gal and Figure 3—figure supplement 1A; compare to Figure 2C for WT cells). Notably, entry of the cER into the daughter slt2Δ cells was paralleled by the entry of CPY* aggregates, which contrasts with the ERSU-dependent block in both cER and aggregate inheritance by WT daughter cells (Figure 3D,G, Figure 3—figure supplement 1A for slt2Δ vs 2G, Figure 2—figure supplement 3A for WT). As shown above, CFTR-expressing WT cells only exhibited a block in ER inheritance and CFTR aggregate transmission when treated with Tm (Figure 2—figure supplement 2A,D, and Figure 2—figure supplement 3C: Tm- vs Tm+). However, Tm treatment of CFTR-expressing slt2Δ cells failed to block either ER inheritance (Figure 3B,C, and Figure 3—figure supplement 1B vs Figure 3—figure supplement 1C) or CFTR aggregate entry into the daughter cell (Figure 3E,F,H, and Figure 3—figure supplement 1D). Taken together, these data revealed that ER inheritance, which is ultimately regulated by the ERSU pathway, regulates protein aggregate transmission into the daughter cell.10.7554/eLife.06970.008Figure 3.Inheritance of ER protein aggregates is ERSU dependent.


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

Piña FJ, Niwa M - Elife (2015)

Colocalization of ER and CPY* or CFTR in slt2Δ cells.(A) Representative field of Hmg1-GFP-expressing slt2Δ cells treated with galactose (Gal) for 2 hr to induce expression of CPY*-mRFP. (B) Representative field of DsRed-HDEL-expressing cells treated with 100 μM copper (Cu) for 2 hr to induce expression of GFP-CFTR. (C) Representative field of DsRed-HDEL-expressing cells treated with 100 μM copper (Cu) and Tm for 2 hr to induce expression of GFP-CFTR. Note that slt2Δ cells do not exhibit a block in ER inheritance under ER stress. (D) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III cells.DOI:http://dx.doi.org/10.7554/eLife.06970.009
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fig3s1: Colocalization of ER and CPY* or CFTR in slt2Δ cells.(A) Representative field of Hmg1-GFP-expressing slt2Δ cells treated with galactose (Gal) for 2 hr to induce expression of CPY*-mRFP. (B) Representative field of DsRed-HDEL-expressing cells treated with 100 μM copper (Cu) for 2 hr to induce expression of GFP-CFTR. (C) Representative field of DsRed-HDEL-expressing cells treated with 100 μM copper (Cu) and Tm for 2 hr to induce expression of GFP-CFTR. Note that slt2Δ cells do not exhibit a block in ER inheritance under ER stress. (D) Distribution of CPY*-mRFP aggregates per bud in all (Total), class I, and class II + III cells.DOI:http://dx.doi.org/10.7554/eLife.06970.009
Mentions: We reasoned that if the ERSU pathway-dependent ER inheritance regulates the distribution of protein aggregates to the daughter cell, then cells lacking the ERSU pathway should also show diminished retention of protein aggregates in the mother cell. To test this, we examined the distribution of CFTR and CPY* aggregates in slt2Δ cells, which are incapable of blocking ER inheritance in response to ER stress. We reported previously that Tm (1 μg/ml) treatment does not block cER inheritance in slt2Δ cells (Babour et al., 2010) and this was also observed in slt2Δ cells when ER stress was induced by CPY* aggregate expression (Figure 3A +Gal and Figure 3—figure supplement 1A; compare to Figure 2C for WT cells). Notably, entry of the cER into the daughter slt2Δ cells was paralleled by the entry of CPY* aggregates, which contrasts with the ERSU-dependent block in both cER and aggregate inheritance by WT daughter cells (Figure 3D,G, Figure 3—figure supplement 1A for slt2Δ vs 2G, Figure 2—figure supplement 3A for WT). As shown above, CFTR-expressing WT cells only exhibited a block in ER inheritance and CFTR aggregate transmission when treated with Tm (Figure 2—figure supplement 2A,D, and Figure 2—figure supplement 3C: Tm- vs Tm+). However, Tm treatment of CFTR-expressing slt2Δ cells failed to block either ER inheritance (Figure 3B,C, and Figure 3—figure supplement 1B vs Figure 3—figure supplement 1C) or CFTR aggregate entry into the daughter cell (Figure 3E,F,H, and Figure 3—figure supplement 1D). Taken together, these data revealed that ER inheritance, which is ultimately regulated by the ERSU pathway, regulates protein aggregate transmission into the daughter cell.10.7554/eLife.06970.008Figure 3.Inheritance of ER protein aggregates is ERSU dependent.

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