title: Uncovering a Dual Regulatory Role for Caspases During Endoplasmic Reticulum Stress-induced Cell Death.
abstract: Many diseases are associated with endoplasmic reticulum (ER) stress, which results from an accumulation of misfolded proteins. This triggers an adaptive response called the "unfolded protein response" (UPR), and prolonged exposure to ER stress leads to cell death. Caspases are reported to play a critical role in ER stress-induced cell death but the underlying mechanisms by which they exert their effect continue to remain elusive. To understand the role caspases play during ER stress, a systems level approach integrating analysis of the transcriptome, proteome, and proteolytic substrate profile was employed. This quantitative analysis revealed transcriptional profiles for most human genes, provided information on protein abundance for 4476 proteins, and identified 445 caspase substrates. Based on these data sets many caspase substrates were shown to be downregulated at the protein level during ER stress suggesting caspase activity inhibits their cellular function. Additionally, RNA sequencing revealed a role for caspases in regulation of ER stress-induced transcriptional pathways and gene set enrichment analysis showed expression of multiple gene targets of essential transcription factors to be upregulated during ER stress upon inhibition of caspases. Furthermore, these transcription factors were degraded in a caspase-dependent manner during ER stress. These results indicate that caspases play a dual role in regulating the cellular response to ER stress through both post-translational and transcriptional regulatory mechanisms. Moreover, this study provides unique insight into progression of the unfolded protein response into cell death, which may help identify therapeutic strategies to treat ER stress-related diseases.
authors.affiliation: From the Departments of ‡Protein Chemistry, lill.jennie@gene.com anania.veronica@gene.com.
authors.forename: Veronica G
authors.initials: VG
authors.lastname: Anania
authors.affiliation: From the Departments of ‡Protein Chemistry.
authors.forename: Kebing
authors.initials: K
authors.lastname: Yu
authors.affiliation: §Bioinformatics and Computational Biology.
authors.forename: Florian
authors.initials: F
authors.lastname: Gnad
authors.affiliation: From the Departments of ‡Protein Chemistry.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Pferdehirt
authors.affiliation: ¶Molecular Oncology.
authors.forename: Han
authors.initials: H
authors.lastname: Li
authors.affiliation: From the Departments of ‡Protein Chemistry.
authors.forename: Taylur P
authors.initials: TP
authors.lastname: Ma
authors.affiliation: From the Departments of ‡Protein Chemistry.
authors.forename: Diana
authors.initials: D
authors.lastname: Jeon
authors.affiliation: ‖Departments of Oral Biological and Medical Sciences, and University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Fortelny
authors.affiliation: **Biostatistics, Genentech, Inc., South San Francisco, CA.
authors.forename: William
authors.initials: W
authors.lastname: Forrest
authors.affiliation: ¶Molecular Oncology.
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
authors.affiliation: ‖Departments of Oral Biological and Medical Sciences, and University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Overall
authors.affiliation: From the Departments of ‡Protein Chemistry, lill.jennie@gene.com anania.veronica@gene.com.
authors.forename: Jennie R
authors.initials: JR
authors.lastname: Lill
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D059748:Proteolysis; D040901:Proteomics / Q000379:methods*; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics; D056811:Unfolded Protein Response
chemical_list: D014157:Transcription Factors; D020169:Caspases