Control of Nonapoptotic Developmental Cell Death in
            <i>Caenorhabditis elegans</i>
            by a Polyglutamine-Repeat Protein

Blum, Elyse S.; Abraham, Mary C.; Yoshimura, Satoshi; Lu, Yun; Shaham, Shai

doi:10.1126/science.1215156

Cited by 68 publications

(104 citation statements)

References 64 publications

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“…Furthermore, the engulfment of the linker cell corpse is independent of known engulfment genes (Ellis and Horvitz 1986;Abraham et al 2007;Blum et al 2012). Consistent with the notion that the death of the linker cell occurs through a nonapoptotic process, dying linker cells do not display the morphological features that are characteristic of apoptotic cells that die during C. elegans development (Abraham et al 2007;Blum et al 2012). Dying linker cells maintain the morphology of healthy cells even during the engulfment process and no condensation of chromatin can be observed in the nucleus.…”

Section: Nonapoptotic Cell Deathsupporting

confidence: 54%

“…Interestingly, similar morphological features have been observed in two different contexts in the vertebrate nervous system: in neurons that die during the development of the spinal cord and ciliary ganglia, and during polyglutamine-induced neurodegeneration. This suggests that this nonapoptotic form of programmed cell death is conserved from C. elegans to mammals (Abraham et al 2007;Blum et al 2012).…”

Section: Nonapoptotic Cell Deathmentioning

confidence: 95%

“…However, for at least one programmed cell death, the death of the "linker cell" in males, the activation phase occurs through a nonapoptotic machinery (Abraham et al 2007;Blum et al 2012). In the following, we will review our current understanding of the specification, activation, and execution phases of apoptotic developmental cell deaths.…”

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confidence: 99%

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Programmed Cell Death DuringCaenorhabditis elegansDevelopment

Conradt

Xue

2016

Genetics

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Programmed cell death is an integral component of Caenorhabditis elegans development. Genetic and reverse genetic studies in C. elegans have led to the identification of many genes and conserved cell death pathways that are important for the specification of which cells should live or die, the activation of the suicide program, and the dismantling and removal of dying cells. Molecular, cell biological, and biochemical studies have revealed the underlying mechanisms that control these three phases of programmed cell death. In particular, the interplay of transcriptional regulatory cascades and networks involving multiple transcriptional regulators is crucial in activating the expression of the key death-inducing gene egl-1 and, in some cases, the ced-3 gene in cells destined to die. A protein interaction cascade involving EGL-1, CED-9, CED-4, and CED-3 results in the activation of the key cell death protease CED-3, which is tightly controlled by multiple positive and negative regulators. The activation of the CED-3 caspase then initiates the cell disassembly process by cleaving and activating or inactivating crucial CED-3 substrates; leading to activation of multiple cell death execution events, including nuclear DNA fragmentation, mitochondrial elimination, phosphatidylserine externalization, inactivation of survival signals, and clearance of apoptotic cells. Further studies of programmed cell death in C. elegans will continue to advance our understanding of how programmed cell death is regulated, activated, and executed in general.KEYWORDS Caenorhabditis elegans; activation phase; execution phase; programmed cell death; specification phase; WormBook

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Section: Nonapoptotic Cell Deathsupporting

confidence: 54%

Section: Nonapoptotic Cell Deathmentioning

confidence: 95%

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Programmed Cell Death DuringCaenorhabditis elegansDevelopment

Conradt

Xue

2016

Genetics

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“…To identify elements within the SARM1 TIR domain responsible for NAD + loss and cell death, we first investigated whether this TIR activity is conserved in a distant SARM1 relative. The SARM1 ortholog in C. elegans, tir-1, is implicated in nonapoptotic cell death in development and motor neuron degeneration in a model of ALS (18,19), suggesting a conserved role in neurodegeneration. However, tir-1 regulates developmental patterning in the nervous system as well as stimulating innate immune signaling in response to pathogens (11,20,21), two activities that appear inconsistent with the neurodestructive properties of human SARM1.…”

Section: Resultsmentioning

confidence: 99%

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Summers

Gibson

DiAntonio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

121

125

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Axon injury in response to trauma or disease stimulates a selfdestruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD + and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD + loss and axon degeneration. Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD + loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD + loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.A xon degeneration in response to injury or disease is a hallmark of neurological disorders of the peripheral and central nervous systems. Akin to programmed cell death pathways, such as apoptosis, axon injury in response to disease or trauma stimulates a local signaling cascade that executes destruction of the injured axon segment (1). Despite growing attention, the molecular details of this prodegenerative cascade are still unclear. A more substantial understanding of the molecular factors that participate in this axon destructive process will likely provide new therapeutic strategies for peripheral neuropathies and other neurodegenerative conditions.Genetic screens in invertebrate and vertebrate model systems identified the Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) as a conserved, fundamental executioner of pathological axon destruction (2, 3). After nerve injury, SARM1 is required for the precipitous loss of the metabolite NAD + (4). Augmenting NAD + biosynthetic pathways protects injured axons from degeneration, suggesting this step is crucial in axonal breakdown (5, 6). In addition to local axon degeneration, SARM1 promotes neuronal cell death in response to mitochondrial toxins, oxygen gluc...

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“…Deregulation of programmed cell death contributes to the development of multiple human diseases, such as cancer and neurodegeneration. While apoptosis is the best-studied form of programmed cell death, recent studies demonstrate that there are also programmed cell death processes that are not apoptosis [4][5][6][7]. For example, necroptosis and ferroptosis are two distinct regulated necrosis pathways that are under precise genetic control and may function under diverse physiological and pathological contexts [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Ferroptosis is an autophagic cell death process

et al. 2016

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Ferroptosis is an iron-dependent form of regulated necrosis. It is implicated in various human diseases, including ischemic organ damage and cancer. Here, we report the crucial role of autophagy, particularly autophagic degradation of cellular iron storage proteins (a process known as ferritinophagy), in ferroptosis. Using RNAi screening coupled with subsequent genetic analysis, we identified multiple autophagy-related genes as positive regulators of ferroptosis. Ferroptosis induction led to autophagy activation and consequent degradation of ferritin and ferritinophagy cargo receptor NCOA4. Consistently, inhibition of ferritinophagy by blockage of autophagy or knockdown of NCOA4 abrogated the accumulation of ferroptosis-associated cellular labile iron and reactive oxygen species, as well as eventual ferroptotic cell death. Therefore, ferroptosis is an autophagic cell death process, and NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis.

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Control of Nonapoptotic Developmental Cell Death in Caenorhabditis elegans by a Polyglutamine-Repeat Protein

Cited by 68 publications

References 64 publications

Programmed Cell Death DuringCaenorhabditis elegansDevelopment

Programmed Cell Death DuringCaenorhabditis elegansDevelopment

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Ferroptosis is an autophagic cell death process

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Control of Nonapoptotic Developmental Cell Death in Caenorhabditis elegans by a Polyglutamine-Repeat Protein

Cited by 68 publications

References 64 publications

Programmed Cell Death DuringCaenorhabditis elegansDevelopment

Programmed Cell Death DuringCaenorhabditis elegansDevelopment

SARM1-specific motifs in the TIR domain enable NAD + loss and regulate injury-induced SARM1 activation

Ferroptosis is an autophagic cell death process

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SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation