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

• Main Authors: Maxime J Kinet, Jennifer A Malin, Mary C Abraham, Elyse S Blum, Melanie R Silverman, Yun Lu, Shai Shaham
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2016-03-01
• Series: eLife
• Subjects: linker cell death; hsf-1; UPS; BTBD2; UBE2D2; let-70
• Online Access: https://elifesciences.org/articles/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.