title: HSF-1 activates the ubiquitin proteasome system to promote non-apoptotic developmental cell death in C. elegans.
abstract: 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.
authors.affiliation: Laboratory of Developmental Genetics, The Rockefeller University, New York, United States.
authors.forename: Maxime J
authors.initials: MJ
authors.lastname: Kinet
authors.affiliation: Laboratory of Developmental Genetics, The Rockefeller University, New York, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Malin
authors.affiliation: Laboratory of Developmental Genetics, The Rockefeller University, New York, United States.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Abraham
authors.affiliation: Laboratory of Developmental Genetics, The Rockefeller University, New York, United States.
authors.forename: Elyse S
authors.initials: ES
authors.lastname: Blum
authors.affiliation: Laboratory of Developmental Genetics, The Rockefeller University, New York, United States.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Silverman
authors.affiliation: Laboratory of Developmental Genetics, The Rockefeller University, New York, United States.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Laboratory of Developmental Genetics, The Rockefeller University, New York, United States.
authors.forename: Shai
authors.identifier: http://orcid.org/0000-0002-3751-975X
authors.initials: S
authors.lastname: Shaham
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D016923:Cell Death; D018507:Gene Expression Regulation, Developmental; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D014157:Transcription Factors; D025801:Ubiquitin; C474710:heat shock factor-1, C elegans; D046988:Proteasome Endopeptidase Complex
keywords: <i>c. elegans</i>; BTBD2; UBE2D2; UPS; cell biology; developmental biology; hsf-1; let-70; linker cell death; stem cells