HSF-1 activates the ubiquitin proteasome system to promote non-apoptotic developmental cell death in C. elegans

• Published in: eLife Vol. 5
• Main Authors: Kinet, Maxime J, Malin, Jennifer A, Abraham, Mary C, Blum, Elyse S, Silverman, Melanie R, Lu, Yun, Shaham, Shai
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 08.03.2016; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Animals; Apoptosis; BTBD2; Caenorhabditis elegans; Caenorhabditis elegans - growth & development; Caenorhabditis elegans Proteins - metabolism; Cell Biology; Cell Death; Culling; Developmental Biology and Stem Cells; Drosophila; Gene Expression Regulation, Developmental; Genes; Heat shock factors; Heat shock proteins; hsf-1; Insects; let-70; linker cell death; Males; MAP kinase; Morphology; Physiological aspects; Physiology; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein kinase; Proteins; Signal Transduction; Transcription factors; Transcription Factors - metabolism; UBE2D2; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-proteasome system; Ubiquitin-protein ligase; UPS; Wnt protein; c. elegans; hsf-1; linker cell death; stem cells; cell biology; UBE2D2; developmental biology; BTBD2; UPS; let-70
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.12821

Apoptosis is a prominent metazoan cell death form. Yet, mutations in apoptosis regulators cause only minor defects in vertebrate development, suggesting that another developmental cell death mechanism exists. While some non-apoptotic programs have been molecularly characterized, none appear to control developmental cell culling. Linker-cell-type death (LCD) is a morphologically conserved non-apoptotic cell death process operating in Caenorhabditis elegans and vertebrate development, and is therefore a compelling candidate process complementing apoptosis. However, the details of LCD execution are not known. Here we delineate a molecular-genetic pathway governing LCD in C. elegans. Redundant activities of antagonistic Wnt signals, a temporal control pathway, and mitogen-activated protein kinase kinase signaling control heat shock factor 1 (HSF-1), a conserved stress-activated transcription factor. Rather than protecting cells, HSF-1 promotes their demise by activating components of the ubiquitin proteasome system, including the E2 ligase LET-70/UBE2D2 functioning with E3 components CUL-3, RBX-1, BTBD-2, and SIAH-1. Our studies uncover design similarities between LCD and developmental apoptosis, and provide testable predictions for analyzing LCD in vertebrates.