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The absence of specific yeast heat-shock proteins leads to abnormal aggregation and compromised autophagic clearance of mutant Huntingtin proteins

Higgins, Ryan, Kabbaj, Marie-Helene, Hatcher, Alexa, Wang, Yanchang·2018·PLOS ONE
DOI 10.1371/journal.pone.0191490PMC PMC5773196
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Fig 1 Cytosolic Hsp70 nucleotide exchange factors Sse1 and Fes1 are required for Htt103QP inclusion body (IB) formation. (A) Htt103QP overexpression and the growth of WT and sse1Δ cells. Cells containing PGALFlag-Htt103QP-GFP were grown to saturation, 10-fold diluted, and spotted onto glucose (YPD) or galactose (YEPG) (yeast extract peptone and galactose) plates. The plates were incubated at 30°C for 2 days. (B) Confocal DIC and fluorescent images showing Htt103QP IB formation. WT and sse1Δ cells with PGALFlag-Htt103QP-GFP were incubated at 30°C in YEPG medium for 16 hrs to induce Htt103QP-GFP expression. The cells were fixed by paraformaldehyde for 5 min and then resuspended in PBS buffer for confocal microscopy. Scale bar = 5μm. (C) 2.5-D analysis showing the intensity of fluorescent GFP peaks of the images from (B). Software used was Zen Blue from Zeiss. (D) Htt103QP IB formation in yeast mutants lacking Hsp70 nucleotide exchange factors (NEFs). Cells with the indicated genotypes were grown and treated as described above and then examined using an EVOS fluorescence microscope. Representative fluorescent images are shown for WT, snl1Δ, sse1Δ, sse2Δ, fes1Δ, and sse1Δ fes1Δ cells expressing Htt103QP-GFP. Scale bar = 5μm. (E) Cells from (D) were quantified for the number of aggregates in each cell: 1, 2 or >2 (n = 100 cells). The results are the average of three independent experiments. (F) The average number of aggregates in WT, sse1Δ, fes1Δ, and sse1Δ fes1Δ cells from (D) were quantified (n > 40 cells). The results are the average of three independent experiments. * indicates statistical comparison between WT and mutants. p < .0001 in all instances.
Fig 1 Cytosolic Hsp70 nucleotide exchange factors Sse1 and Fes1 are required for Htt103QP inclusion body (IB) formation. (A) Htt103QP overexpression and the growth of WT and sse1Δ cells. Cells containing PGALFlag-Htt103QP-GFP were grown to saturation, 10-fold diluted, and spotted onto glucose (YPD) or galactose (YEPG) (yeast extract peptone and galactose) plates. The plates were incubated at 30°C for 2 days. (B) Confocal DIC and fluorescent images showing Htt103QP IB formation. WT and sse1Δ cells with PGALFlag-Htt103QP-GFP were incubated at 30°C in YEPG medium for 16 hrs to induce Htt103QP-GFP expression. The cells were fixed by paraformaldehyde for 5 min and then resuspended in PBS buffer for confocal microscopy. Scale bar = 5μm. (C) 2.5-D analysis showing the intensity of fluorescent GFP peaks of the images from (B). Software used was Zen Blue from Zeiss. (D) Htt103QP IB formation in yeast mutants lacking Hsp70 nucleotide exchange factors (NEFs). Cells with the indicated genotypes were grown and treated as described above and then examined using an EVOS fluorescence microscope. Representative fluorescent images are shown for WT, snl1Δ, sse1Δ, sse2Δ, fes1Δ, and sse1Δ fes1Δ cells expressing Htt103QP-GFP. Scale bar = 5μm. (E) Cells from (D) were quantified for the number of aggregates in each cell: 1, 2 or >2 (n = 100 cells). The results are the average of three independent experiments. (F) The average number of aggregates in WT, sse1Δ, fes1Δ, and sse1Δ fes1Δ cells from (D) were quantified (n > 40 cells). The results are the average of three independent experiments. * indicates statistical comparison between WT and mutants. p < .0001 in all instances.CC BY · PubMed Central
Fig 2 Cells lacking Sse1 and Fes1 exhibit accelerated Htt103QP aggregate formation. (A) WT, sse1Δ, and fes1Δ cells with PGALFlag-Htt103QP-GFP plasmid were grown in non-inducible raffinose medium (YEP + Raffinose) to mid log phase, and then galactose was added to induce the overexpression of Flag-Htt103QP-GFP. Cells were collected every hour for microscopy using the EVOS microscope. Representative DIC and fluorescence images are shown for Htt103QP aggregate formation. Scale bar = 5μm. The number of aggregates in each cell were quantified. The percentage of cells with 1, 2 or >2 aggregates (n = 100 cells) is shown. (B) Quantitation of the average number of aggregates per cell in WT, sse1Δ and fes1Δ cells. Averages are from three independent experiments (n > 50 cells). (C) Detection of Htt103QP protein aggregates using agarose gel electrophoresis. WT and mutant cells were grown in non-inducible raffinose medium (R). After galactose addition, the cells were incubated for 3 hr (G). Protein samples were prepared as described in Materials and Methods and subjected to SDS agarose gel electrophoresis (SDS-AGE) and SDS-PAGE. Two separate WT and sse1Δ strains are shown for reproducibility (left). The results for WT, sse2Δ, fes1Δ, and snl1Δ mutants are shown in the right panel. Pgk1: loading control.
Fig 2 Cells lacking Sse1 and Fes1 exhibit accelerated Htt103QP aggregate formation. (A) WT, sse1Δ, and fes1Δ cells with PGALFlag-Htt103QP-GFP plasmid were grown in non-inducible raffinose medium (YEP + Raffinose) to mid log phase, and then galactose was added to induce the overexpression of Flag-Htt103QP-GFP. Cells were collected every hour for microscopy using the EVOS microscope. Representative DIC and fluorescence images are shown for Htt103QP aggregate formation. Scale bar = 5μm. The number of aggregates in each cell were quantified. The percentage of cells with 1, 2 or >2 aggregates (n = 100 cells) is shown. (B) Quantitation of the average number of aggregates per cell in WT, sse1Δ and fes1Δ cells. Averages are from three independent experiments (n > 50 cells). (C) Detection of Htt103QP protein aggregates using agarose gel electrophoresis. WT and mutant cells were grown in non-inducible raffinose medium (R). After galactose addition, the cells were incubated for 3 hr (G). Protein samples were prepared as described in Materials and Methods and subjected to SDS agarose gel electrophoresis (SDS-AGE) and SDS-PAGE. Two separate WT and sse1Δ strains are shown for reproducibility (left). The results for WT, sse2Δ, fes1Δ, and snl1Δ mutants are shown in the right panel. Pgk1: loading control.CC BY · PubMed Central
Fig 3 Hsp70 and Hsp40 chaperones participate in Htt103QP IB formation. (A) Htt103QP IB formation in yeast Hsp70 Ssa family mutants. Fluorescent images of SSA1-WT and SSA1-45 cells expressing Flag-Htt103QP-GFP at 35°C for 16 hr. Two separate fluorescent images for ssa1-45 mutants indicate two phenotypes. Scale bar = 5μm. (B) Htt103QP IB formation in Hsp40 co-chaperone mutant ydj1-151. Fluorescent images of WT and ydj1-151 cells expressing Flag-Htt103QP-GFP for 16 hrs at permissive (25°C) and semi-permissive (30°C) temperatures. Cells were quantified for the number of aggregates in each cell: 1, 2 or >2 (n = 100 cells). The results are the average of three independent experiments. Scale bar = 5μm. (C) Htt103QP IB formation in Hsp40 co-chaperone mutant sis1-85. Fluorescent images of SIS1-HA and SIS1-85-HA strains expressing Htt103QP-GFP for 16 hrs at permissive (25°C) and restrictive (37°C) temperatures. Scale bar = 5μm. All microscopy in this figure was performed on the EVOS microscope.
Fig 3 Hsp70 and Hsp40 chaperones participate in Htt103QP IB formation. (A) Htt103QP IB formation in yeast Hsp70 Ssa family mutants. Fluorescent images of SSA1-WT and SSA1-45 cells expressing Flag-Htt103QP-GFP at 35°C for 16 hr. Two separate fluorescent images for ssa1-45 mutants indicate two phenotypes. Scale bar = 5μm. (B) Htt103QP IB formation in Hsp40 co-chaperone mutant ydj1-151. Fluorescent images of WT and ydj1-151 cells expressing Flag-Htt103QP-GFP for 16 hrs at permissive (25°C) and semi-permissive (30°C) temperatures. Cells were quantified for the number of aggregates in each cell: 1, 2 or >2 (n = 100 cells). The results are the average of three independent experiments. Scale bar = 5μm. (C) Htt103QP IB formation in Hsp40 co-chaperone mutant sis1-85. Fluorescent images of SIS1-HA and SIS1-85-HA strains expressing Htt103QP-GFP for 16 hrs at permissive (25°C) and restrictive (37°C) temperatures. Scale bar = 5μm. All microscopy in this figure was performed on the EVOS microscope.CC BY · PubMed Central
Fig 4 Hsp104-GFP positive aggregates are increased in sse1Δ and ydj1-151 mutants. (A) Hsp104 recruitment to Htt103QP aggregates is independent of chaperones. Cell with indicated genotypes were grown in non-inducible raffinose medium to mid-log phase then galactose was added. Images were taken after incubation for 3 hr. Representative fluorescence images show cellular localization of Hsp104-GFP and Htt103QP-mApple. DIC and merged images are also shown. Scale bar = 5μm. (B) Constitutive appearance of Hsp104-GFP positive aggregates in sse1Δ and ydj1-151 mutants. Cells with indicated genotypes were grown in raffinose or galactose containing medium to mid-log phase. Representative fluorescence images are shown. WT cells show predominantly nuclear localized Hsp104-GFP in the absence of Htt103QP overexpression. Scale bar = 5μm. (C) Cells from (B) were quantified based on the presence of Hsp104-GFP positive aggregate(s). Results are the average of three independent experiments (n = 100 cells). All images in this figure was obtained using the EVOS microscope.
Fig 4 Hsp104-GFP positive aggregates are increased in sse1Δ and ydj1-151 mutants. (A) Hsp104 recruitment to Htt103QP aggregates is independent of chaperones. Cell with indicated genotypes were grown in non-inducible raffinose medium to mid-log phase then galactose was added. Images were taken after incubation for 3 hr. Representative fluorescence images show cellular localization of Hsp104-GFP and Htt103QP-mApple. DIC and merged images are also shown. Scale bar = 5μm. (B) Constitutive appearance of Hsp104-GFP positive aggregates in sse1Δ and ydj1-151 mutants. Cells with indicated genotypes were grown in raffinose or galactose containing medium to mid-log phase. Representative fluorescence images are shown. WT cells show predominantly nuclear localized Hsp104-GFP in the absence of Htt103QP overexpression. Scale bar = 5μm. (C) Cells from (B) were quantified based on the presence of Hsp104-GFP positive aggregate(s). Results are the average of three independent experiments (n = 100 cells). All images in this figure was obtained using the EVOS microscope.CC BY · PubMed Central
Fig 5 The autophagic degradation of Htt103QP is compromised in sse1Δ and fes1Δ mutants. (A) The autophagic disposal of Htt103QP in WT and sse1Δ mutant cells. pep4Δ VPH1-mApple (WT) and sse1Δ pep4Δ VPH1-mApple (sse1Δ) cells containing Flag-Htt103QP-GFP were grown in galactose medium (YEPG) at 30°C for 16 hr. Glucose was then added to shut off Htt103QP expression, and 100 mM hydroxyurea (HU) was added to block cell cycle progression. Representative fluorescent images are shown for the localization of Htt103QP-GFP and Vph1-mApple before and after addition of glucose and HU. Vph1-mApple was used to mark vacuole structure. Pep4 is a vacuolar protease, and pep4Δ mutant was used to slow degradation inside the vacuole to enhance visualization. (B) Htt103QP autophagic disposal in WT and fes1Δ mutant cells. A similar protocol was used to examine the vacuolar localization of Htt103QP-GFP. (C and D) Quantitation of cells with Htt103QP IB or aggregates localized outside the vacuole over time. The cells from (A) and (B) are used for the quantitation. The quantified results (three independent repeats) were obtained by counting the number of cells containing at least one IB or aggregate (n = 100). All microscopy in this figure was performed on the EVOS microscope.
Fig 5 The autophagic degradation of Htt103QP is compromised in sse1Δ and fes1Δ mutants. (A) The autophagic disposal of Htt103QP in WT and sse1Δ mutant cells. pep4Δ VPH1-mApple (WT) and sse1Δ pep4Δ VPH1-mApple (sse1Δ) cells containing Flag-Htt103QP-GFP were grown in galactose medium (YEPG) at 30°C for 16 hr. Glucose was then added to shut off Htt103QP expression, and 100 mM hydroxyurea (HU) was added to block cell cycle progression. Representative fluorescent images are shown for the localization of Htt103QP-GFP and Vph1-mApple before and after addition of glucose and HU. Vph1-mApple was used to mark vacuole structure. Pep4 is a vacuolar protease, and pep4Δ mutant was used to slow degradation inside the vacuole to enhance visualization. (B) Htt103QP autophagic disposal in WT and fes1Δ mutant cells. A similar protocol was used to examine the vacuolar localization of Htt103QP-GFP. (C and D) Quantitation of cells with Htt103QP IB or aggregates localized outside the vacuole over time. The cells from (A) and (B) are used for the quantitation. The quantified results (three independent repeats) were obtained by counting the number of cells containing at least one IB or aggregate (n = 100). All microscopy in this figure was performed on the EVOS microscope.CC BY · PubMed Central
Fig 6 Sse1 and Fes1 are required for efficient recognition of Htt103QP by autophagy machinery. (A) The co-localization of Htt103QP and Atg8 in WT, sse1Δ, and fes1Δ cells. Cells containing GFP-ATG8 and PGALFlag-Htt103QP-mApple were grown in galactose medium YEPG for 16 hrs and fixed for microscopy. Representative fluorescence images show the localization of Htt103QP-mApple and GFP-Atg8. Scale bar = 5μm. (B) Quantitation of total number of Htt103QP aggregates colocalized with GFP-Atg8 in WT, sse1Δ, and fes1Δ cells (n = 100 IB/aggregates). Quantities indicate the average of three independent experiments. * indicates statistical comparison. p < .001. (C) Quantitation of the number of GFP-Atg8 autophagosomes present in WT, sse1Δ and fes1Δ cells incubated in glucose or galactose medium (n = 100 cells). Quantities indicate the average of three independent experiments. (D) Sse1 and Fes1 are not required for starvation-induced autophagy. WT, sse1Δ, and fes1Δ cells with GFP-ATG8 were grown in SC -TRP medium, and then shifted to nitrogen-deficient medium (SD-N) for 24 hr. The cells were collected to detect the presence of GFP-Atg8 and the cleavage product, monomeric GFP, using anti-GFP antibody. Pgk1: loading control. The EVOS microscope was used to obtain the images in this figure.
Fig 6 Sse1 and Fes1 are required for efficient recognition of Htt103QP by autophagy machinery. (A) The co-localization of Htt103QP and Atg8 in WT, sse1Δ, and fes1Δ cells. Cells containing GFP-ATG8 and PGALFlag-Htt103QP-mApple were grown in galactose medium YEPG for 16 hrs and fixed for microscopy. Representative fluorescence images show the localization of Htt103QP-mApple and GFP-Atg8. Scale bar = 5μm. (B) Quantitation of total number of Htt103QP aggregates colocalized with GFP-Atg8 in WT, sse1Δ, and fes1Δ cells (n = 100 IB/aggregates). Quantities indicate the average of three independent experiments. * indicates statistical comparison. p < .001. (C) Quantitation of the number of GFP-Atg8 autophagosomes present in WT, sse1Δ and fes1Δ cells incubated in glucose or galactose medium (n = 100 cells). Quantities indicate the average of three independent experiments. (D) Sse1 and Fes1 are not required for starvation-induced autophagy. WT, sse1Δ, and fes1Δ cells with GFP-ATG8 were grown in SC -TRP medium, and then shifted to nitrogen-deficient medium (SD-N) for 24 hr. The cells were collected to detect the presence of GFP-Atg8 and the cleavage product, monomeric GFP, using anti-GFP antibody. Pgk1: loading control. The EVOS microscope was used to obtain the images in this figure.CC BY · PubMed Central
Fig 7 Hsp40 co-chaperone Ydj1 is required for efficient autophagic degradation of Htt103QP. (A) Htt103QP autophagy in WT and ydj1-151 mutant cells. pep4Δ VPH1-mApple (WT) and ydj1-151 pep4Δ VPH1-mApple (ydj1-151) cells containing PGALFlag-Htt103QP-GFP were grown in galactose medium (YEPG) at 25°C for 16 hrs. Cells were then shifted to semi-permissive temperatures (32°C) for 10 min prior to glucose and hydroxyurea (HU) addition. Representative fluorescent images are shown for the localization of Htt103QP-GFP and Vph1-mApple (vacuolar marker) before and after addition of glucose and HU. Scale bar = 5μm. (B) Quantitation of cells with Htt103QP IB or aggregates localized outside the vacuole over time. Results from three independent experiments were used for the quantitation. The quantified results were obtained by counting the number of cells containing at least one IB or aggregate (n = 100). (C) The co-localization of Htt103QP and Atg8 in WT and ydj1-151 cells. Cells containing GFP-ATG8 and PGALFlag-Htt103QP-mApple were grown in galactose medium YEPG for 16 hrs at 32°C and fixed for microscopy. Representative fluorescence images show the localization of Htt103QP-mApple and GFP-Atg8. (D) Quantitation of total number of Htt103QP aggregates colocalized with GFP-Atg8 in WT and ydj1-151 cells (n = 100 IB/aggregates). Quantities indicate the average of three independent experiments. * indicates statistical comparison. p < .005. (E) Quantitation of the number of GFP-Atg8 autophagosomes present in WT and ydj1-151 cells incubated in glucose or galactose medium (n = 100 cells). Quantities indicate the average of three independent experiments. All images in this figure were acquired using the EVOS microscope.
Fig 7 Hsp40 co-chaperone Ydj1 is required for efficient autophagic degradation of Htt103QP. (A) Htt103QP autophagy in WT and ydj1-151 mutant cells. pep4Δ VPH1-mApple (WT) and ydj1-151 pep4Δ VPH1-mApple (ydj1-151) cells containing PGALFlag-Htt103QP-GFP were grown in galactose medium (YEPG) at 25°C for 16 hrs. Cells were then shifted to semi-permissive temperatures (32°C) for 10 min prior to glucose and hydroxyurea (HU) addition. Representative fluorescent images are shown for the localization of Htt103QP-GFP and Vph1-mApple (vacuolar marker) before and after addition of glucose and HU. Scale bar = 5μm. (B) Quantitation of cells with Htt103QP IB or aggregates localized outside the vacuole over time. Results from three independent experiments were used for the quantitation. The quantified results were obtained by counting the number of cells containing at least one IB or aggregate (n = 100). (C) The co-localization of Htt103QP and Atg8 in WT and ydj1-151 cells. Cells containing GFP-ATG8 and PGALFlag-Htt103QP-mApple were grown in galactose medium YEPG for 16 hrs at 32°C and fixed for microscopy. Representative fluorescence images show the localization of Htt103QP-mApple and GFP-Atg8. (D) Quantitation of total number of Htt103QP aggregates colocalized with GFP-Atg8 in WT and ydj1-151 cells (n = 100 IB/aggregates). Quantities indicate the average of three independent experiments. * indicates statistical comparison. p < .005. (E) Quantitation of the number of GFP-Atg8 autophagosomes present in WT and ydj1-151 cells incubated in glucose or galactose medium (n = 100 cells). Quantities indicate the average of three independent experiments. All images in this figure were acquired using the EVOS microscope.CC BY · PubMed Central

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Sorted by citations

Metadata

Authors
Higgins, R., Kabbaj, M.-H., Hatcher, A., & Wang, Y.
ORCID
Wang, Yanchang
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2018-01-18
Volume
13
Issue
1
Pages
e0191490
ISSN
1932-6203
DOI
10.1371/journal.pone.0191490
PMC
PMC5773196
Cited by
22
References
4
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institution of Health (RO1GM102115)
  • Florida State University (CRC planning Grant)

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