المؤلفون: Pandey, Taruna, Zhang, Jianxiu, Wang, Bingying, Ma, Dengke K

مصطلحات موضوعية: Alkuraya-Kučinskas syndrome, C. elegans, bridge-like lipid transfer, membrane contact site, non-vesicular lipid transport, phospholipid, thermal stress, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance

الوصف: In eukaryotic cells, lipid transfer can occur at membrane contact sites (MCS) to facilitate the exchange of various lipids between two adjacent cellular organelle membranes. Lipid transfer proteins (LTPs), including shuttle LTP or bridge-like LTP (BLTP), transport lipids at MCS and are critical for diverse cellular processes, including lipid metabolism, membrane trafficking, and cell signaling. BLTPs (BLTP1-5, including the ATG2 and VPS13 family proteins) contain lipid-accommodating hydrophobic repeating β-groove (RBG) domains that allow the bulk transfer of lipids through MCS. Compared with vesicular lipid transfer and shuttle LTP, BLTPs have been only recently identified. Their functions and regulatory mechanisms are currently being unraveled in various model organisms and by diverse approaches. In this review, we summarize the genetics, structural features, and biological functions of BLTP in the genetically tractable model organism C. elegans. We discuss our recent studies and findings on C. elegans LPD-3, a prototypical megaprotein ortholog of BLTP1, with identified lipid transfer functions that are evolutionarily conserved in multicellular organisms and in human cells. We also highlight areas for future research of BLTP using C. elegans and complementary model systems and approaches. Given the emerging links of BLTP to several human diseases, including Parkinson's disease and Alkuraya-Kučinskas syndrome, discovering evolutionarily conserved roles of BLTPs and their mechanisms of regulation and action should contribute to new advances in basic cell biology and potential therapeutic development for related human disorders.

الوصول الحر: https://escholarship.org/uc/item/10x0f83rTest

المؤلفون: Wang, Bingying, Pandey, Taruna, Long, Yong, Delgado-Rodriguez, Sofia, Daugherty, Matthew, Ma, Dengke

المصدر: Current Biology. 32(22)

مصطلحات موضوعية: C. elegans, EGL-9, HIF-1, amygdalin, cyanide detoxifcation, cysl-1, cysl-2, gene co-option, green algae, horizontal gene transfer, Animals, Caenorhabditis elegans, Amygdalin, Phylogeny, Caenorhabditis elegans Proteins, Cyanides

الوصف: Amygdalin is a cyanogenic glycoside enriched in the tissues of many edible plants, including seeds of stone fruits such as cherry (Prunus avium), peach (Prunus persica), and apple (Malus domestica). These plants biosynthesize amygdalin in defense against herbivore animals, as amygdalin generates poisonous cyanide upon plant tissue destruction.1,2,3,4 Poisonous to many animals, amygdalin-derived cyanide is detoxified by potent enzymes commonly found in bacteria and plants but not most animals.5 Here we show that the nematode C. elegans can detoxify amygdalin by a genetic pathway comprising cysl-1, egl-9, hif-1, and cysl-2. A screen of a natural product library for hypoxia-independent regulators of HIF-1 identifies amygdalin as a potent activator of cysl-2, a HIF-1 transcriptional target that encodes a cyanide detoxification enzyme in C. elegans. As a cysl-2 paralog similarly essential for amygdalin resistance, cysl-1 encodes a protein homologous to cysteine biosynthetic enzymes in bacteria and plants but functionally co-opted in C. elegans. We identify exclusively HIF-activating egl-9 mutations in a cysl-1 suppressor screen and show that cysl-1 confers amygdalin resistance by regulating HIF-1-dependent cysl-2 transcription to protect against amygdalin toxicity. Phylogenetic analysis indicates that cysl-1 and cysl-2 were likely acquired from green algae through horizontal gene transfer (HGT) and functionally co-opted in protection against amygdalin. Since acquisition, these two genes evolved division of labor in a cellular circuit to detect and detoxify cyanide. Thus, algae-to-nematode HGT and subsequent gene function co-option events may facilitate host survival and adaptation to adverse environmental stresses and biogenic toxins.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/120997svTest
https://escholarship.org/content/qt120997sv/qt120997sv.pdfTest

المؤلفون: Wang, Xin, Jiang, Wei, Luo, Shuo, Yang, Xiaoyu, Wang, Changnan, Wang, Bingying, Dang, Yongjun, Shen, Yin, Ma, Dengke K

المصدر: Molecular Brain. 14(1)

مصطلحات موضوعية: Genetics, Neurosciences, Brain Disorders, Mental Health, Aetiology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Underpinning research, Actins, Animals, Biological Evolution, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cell Shape, Conserved Sequence, Cytoskeleton, Dopaminergic Neurons, Gain of Function Mutation, Genes, Reporter, HEK293 Cells, Humans, Loss of Function Mutation, Membrane Proteins, Morphogenesis, Multigene Family, Multiprotein Complexes, Neurogenesis, Panic Disorder, Protein Domains, Protein Interaction Mapping, Recombinant Fusion Proteins, Sensory Receptor Cells, Two-Hybrid System Techniques, TMEM132D, Panic disorder, WAVE regulatory complex, Actin, C, elegans, C. elegans, Medical and Health Sciences, Neurology & Neurosurgery

الوصف: TMEM132D is a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders. Defining a conserved family of transmembrane proteins, TMEM132D and its homologs are still of unknown molecular functions. By generating loss-of-function mutants of the sole TMEM132 ortholog in C. elegans, we identify abnormal morphologic phenotypes in the dopaminergic PDE neurons. Using a yeast two-hybrid screen, we find that NAP1 directly interacts with the cytoplasmic domain of human TMEM132D, and mutations in C. elegans tmem-132 that disrupt interaction with NAP1 cause similar morphologic defects in the PDE neurons. NAP1 is a component of the WAVE regulatory complex (WRC) that controls F-actin cytoskeletal dynamics. Decreasing activity of WRC rescues the PDE defects in tmem-132 mutants, whereas gain-of-function of TMEM132D in mammalian cells inhibits WRC, leading to decreased abundance of select WRC components, impaired actin nucleation and cell motility. We propose that metazoan TMEM132 family proteins play evolutionarily conserved roles in regulating NAP1 protein homologs to restrict inappropriate WRC activity, cytoskeletal and morphologic changes in the cell.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2ds8c4f7Test

المؤلفون: Jiang, Wei, Wei, Yuehua, Long, Yong, Owen, Arthur, Wang, Bingying, Wu, Xuebing, Luo, Shuo, Dang, Yongjun, Ma, Dengke K

مصطلحات موضوعية: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Gene Expression Regulation, Basic-Leucine Zipper Transcription Factors, Gene Regulatory Networks, Cold Temperature, Stress, Physiological, C. elegans, C. elegans screen, ISY1 or ISY-1, ZIP-10, bZIP transcription factor, chromosomes, forward genetics, gene expression, hypothermia, Biochemistry and Cell Biology

الوصف: How multicellular organisms respond to and are impacted by severe hypothermic stress is largely unknown. From C. elegans screens for mutants abnormally responding to cold-warming stimuli, we identify a molecular genetic pathway comprising ISY-1, a conserved uncharacterized protein, and ZIP-10, a bZIP-type transcription factor. ISY-1 gatekeeps the ZIP-10 transcriptional program by regulating the microRNA mir-60. Downstream of ISY-1 and mir-60, zip-10 levels rapidly and specifically increase upon transient cold-warming exposure. Prolonged zip-10 up-regulation induces several protease-encoding genes and promotes stress-induced organismic death, or phenoptosis, of C. elegans. zip-10 deficiency confers enhanced resistance to prolonged cold-warming stress, more prominently in adults than larvae. We conclude that the ZIP-10 genetic program mediates cold-warming response and may have evolved to promote wild-population kin selection under resource-limiting and thermal stress conditions.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3960v953Test

المؤلفون: Vozdek, Roman, Wang, Bingying, Li, Kathy H., Pramstaller, Peter P., Hicks, Andrew A., Ma, Dengke K.

المصدر: Open Research Europe

مصطلحات موضوعية: Parkinson's disease, Parkin, Synuclein, genetic screen, RNA interference, autophagy, C. elegans

الوصف: Background: Parkin, which when mutated leads to early-onset Parkinson's disease, acts as an E3 ubiquitin ligase. How Parkin is regulated for selective protein and organelle targeting is not well understood. Here, we used protein interactor and genetic screens in Caenorhabditis elegans ( C. elegans) to identify new regulators of Parkin abundance and showed their impact on autophagy-lysosomal dynamics and alpha-Synuclein processing. Methods: We generated a transgene encoding mCherry-tagged C. elegans Parkin – Parkinson's Disease Related 1 (PDR-1). We performed protein interactor screen using Co-immunoprecipitation followed by mass spectrometry analysis to identify putative interacting partners of PDR-1. Ribonucleic acid interference (RNAi) screen and an unbiased mutagenesis screen were used to identify genes regulating PDR-1 abundance. Confocal microscopy was used for the identification of the subcellular localization of PDR-1 and alpha-Synuclein processing. Results: We show that the mCherry::pdr-1 transgene rescues the mitochondrial phenotype of pdr-1 mutants and that the expressed PDR-1 reporter is localized in the cytosol with enriched compartmentalization in the autophagy-lysosomal system. We determined that the transgenic overexpression of the PDR-1 reporter, due to inactivated small interfering RNA (siRNA) generation pathway, disrupts autophagy-lysosomal dynamics. From the RNAi screen of putative PDR-1 interactors we found that the inactivated Adenine Nucleotide Translocator ant-1.1/hANT, or hybrid ubiquitin genes ubq-2/h UBA52 and ubl-1/h RPS27A encoding a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively, induced PDR-1 abundance and affected lysosomal dynamics. In addition, we demonstrate that the abundant PDR-1 plays a role in alpha-Synuclein processing. Conclusions: These data show that the abundant C. elegans Parkin ortholog affects the autophagy-lysosomal system together with alpha-Synuclein processing which can help in understanding the pathology in Parkin-related ...

العلاقة: https://zenodo.org/record/8412752Test; https://doi.org/10.12688/openreseurope.14235.1Test; oai:zenodo.org:8412752

الإتاحة: https://doi.org/10.12688/openreseurope.14235.1Test
https://doi.org/10.1038/77060Test
https://doi.org/10.1002/humu.21277Test
https://doi.org/10.1101/cshperspect.a011338Test
https://doi.org/10.1093/hmg/ddg328Test
https://doi.org/10.1111/febs.13249Test
https://doi.org/10.1083/jcb.200809125Test
https://doi.org/10.15252/embr.201540352Test
https://doi.org/10.1038/s41586-018-0224-xTest
https://doi.org/10.1038/nature13392Test

المؤلفون: Wang, Bingying, Pandey, Taruna, Long, Yong, Delgado-Rodriguez, Sofia, Ma, Dengke, Daugherty, Matthew

المصدر: Current Biology, vol 32, iss 22

مصطلحات موضوعية: C. elegans, EGL-9, HIF-1, amygdalin, cyanide detoxifcation, cysl-1, cysl-2, gene co-option, green algae, horizontal gene transfer, Animals, Caenorhabditis elegans, Phylogeny, Caenorhabditis elegans Proteins, Cyanides

الوصف: Amygdalin is a cyanogenic glycoside enriched in the tissues of many edible plants, including seeds of stone fruits such as cherry (Prunus avium), peach (Prunus persica), and apple (Malus domestica). These plants biosynthesize amygdalin in defense against herbivore animals, as amygdalin generates poisonous cyanide upon plant tissue destruction.1,2,3,4 Poisonous to many animals, amygdalin-derived cyanide is detoxified by potent enzymes commonly found in bacteria and plants but not most animals.5 Here we show that the nematode C.elegans can detoxify amygdalin by a genetic pathway comprising cysl-1, egl-9, hif-1, and cysl-2. A screen of a natural product library for hypoxia-independent regulators of HIF-1 identifies amygdalin as a potent activator of cysl-2, a HIF-1 transcriptional target that encodes a cyanide detoxification enzyme in C.elegans. As a cysl-2 paralog similarly essential for amygdalin resistance, cysl-1 encodes a protein homologous to cysteine biosynthetic enzymes in bacteria and plants but functionally co-opted in C.elegans. We identify exclusively HIF-activating egl-9 mutations in a cysl-1 suppressor screen and show that cysl-1 confers amygdalin resistance by regulating HIF-1-dependent cysl-2 transcription to protect against amygdalin toxicity. Phylogenetic analysis indicates that cysl-1 and cysl-2 were likely acquired from green algae through horizontal gene transfer (HGT) and functionally co-opted in protection against amygdalin. Since acquisition, these two genes evolved division of labor in a cellular circuit to detect and detoxify cyanide. Thus, algae-to-nematode HGT and subsequent gene function co-option events may facilitate host survival and adaptation to adverse environmental stresses and biogenic toxins.

وصف الملف: application/pdf

العلاقة: qt120997sv; https://escholarship.org/uc/item/120997svTest

الإتاحة: https://escholarship.org/uc/item/120997svTest

المؤلفون: Pandey, Taruna¹ (AUTHOR), Ma, Dengke K.^1,2 (AUTHOR) Dengke.Ma@ucsf.edu

المصدر: Biochemistry (00062979). Dec2022, Vol. 87 Issue 12/13, p1504-1511. 8p.

مصطلحات موضوعية: *CAENORHABDITIS elegans, *MULTICELLULAR organisms, *NATURAL selection, *ABIOTIC stress, *RESOURCE allocation

مستخلص: Evolution by natural selection results in biological traits that enable organismic adaptation and survival under various stressful environments. External stresses can be sometimes too severe to overcome, leading to organismic death either because of failure in adapting to such stress, or alternatively, through a regulated form of organismic death (phenoptosis). While regulated cell deaths, including apoptosis, have been extensively studied, little is known about the molecular and cellular mechanisms underlying phenoptosis and its evolutionary significance for multicellular organisms. In this article, we review documented phenomena and mechanistic evidence emerging from studies of stress-induced phenoptosis in the multicellular organism C. elegans and stress-induced deaths at cellular levels in organisms ranging from bacteria to mammals, focusing on abiotic and pathogen stresses. Genes and signaling pathways involved in phenoptosis appear to promote organismic death during severe stress and aging, while conferring fitness and immune defense during mild stress and early life, consistent with their antagonistic pleiotropy actions. As cell apoptosis during development can shape tissues and organs, stress-induced phenoptosis may also contribute to possible benefits at the population level, through mechanisms including kin selection, abortive infection, and soma-to-germline resource allocation. Current models can generate experimentally testable predictions and conceptual frameworks with implications for understanding both stress-induced phenoptosis and natural aging. [ABSTRACT FROM AUTHOR]

المؤلفون: Vozdek, Roman, Wang, Bingying, Li, Kathy H., Pramstaller, Peter P., Hicks, Andrew A., Ma, Dengke K.

المصدر: Open Research Europe 2023 2:23

مصطلحات موضوعية: Parkinson’s disease, Parkin, Synuclein, genetic screen, RNA interference, autophagy, C. elegans

الوصف: Background: Parkin, which when mutated leads to early-onset Parkinson’s disease, acts as an E3 ubiquitin ligase. How Parkin is regulated for selective protein and organelle targeting is not well understood. Here, we used protein interactor and genetic screens in Caenorhabditis elegans ( C. elegans) to identify new regulators of Parkin abundance and showed their impact on autophagy-lysosomal dynamics and alpha-Synuclein processing. Methods: We generated a transgene encoding mCherry-tagged C. elegans Parkin – Parkinson’s Disease Related 1 (PDR-1). We performed protein interactor screen using Co-immunoprecipitation followed by mass spectrometry analysis to identify putative interacting partners of PDR-1. Ribonucleic acid interference (RNAi) screen and an unbiased mutagenesis screen were used to identify genes regulating PDR-1 abundance. Confocal microscopy was used for the identification of the subcellular localization of PDR-1 and alpha-Synuclein processing. Results:We show that the mCherry::pdr-1 transgene rescues the mitochondrial phenotype of pdr-1 mutants and that the expressed PDR-1 reporter is localized in the cytosol with enriched compartmentalization in the autophagy-lysosomal system. We determined that the transgenic overexpression of the PDR-1 reporter, due to inactivated small interfering RNA (siRNA) generation pathway, disrupts autophagy-lysosomal dynamics. From the RNAi screen of putative PDR-1 interactors we found that the inactivated Adenine Nucleotide Translocator ant-1.1/hANT, or hybrid ubiquitin genes ubq-2/hUBA52 and ubl-1/hRPS27A encoding a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively, induced PDR-1 abundance and affected lysosomal dynamics. In addition, we demonstrate that the abundant PDR-1 plays a role in alpha-Synuclein processing. Conclusions: These data show that the abundant reporter of C. elegans Parkin affects the autophagy-lysosomal system together with alpha-Synuclein processing which can help in understanding the pathology in Parkin-related ...

وصف الملف: text/html

العلاقة: https://doi.org/10.12688/openreseurope.14235.1Test; https://doi.org/10.12688/openreseurope.14235.2Test

الإتاحة: https://doi.org/10.12688/openreseurope.14235.2Test
https://doi.org/10.12688/openreseurope.14235.1Test

المؤلفون: Vozdek, Roman, Wang, Bingying, Li, Kathy H., Pramstaller, Peter P., Hicks, Andrew A., Ma, Dengke K.

المصدر: Open Research Europe 2022 2:23

مصطلحات موضوعية: Parkinson’s disease, Parkin, Synuclein, genetic screen, RNA interference, autophagy, C. elegans

الوصف: Background: Parkin, which when mutated leads to early-onset Parkinson’s disease, acts as an E3 ubiquitin ligase. How Parkin is regulated for selective protein and organelle targeting is not well understood. Here, we used protein interactor and genetic screens in Caenorhabditis elegans ( C. elegans) to identify new regulators of Parkin abundance and showed their impact on autophagy-lysosomal dynamics and alpha-Synuclein processing. Methods: We generated a transgene encoding mCherry-tagged C. elegans Parkin – Parkinson’s Disease Related 1 (PDR-1). We performed protein interactor screen using Co-immunoprecipitation followed by mass spectrometry analysis to identify putative interacting partners of PDR-1. Ribonucleic acid interference (RNAi) screen and an unbiased mutagenesis screen were used to identify genes regulating PDR-1 abundance. Confocal microscopy was used for the identification of the subcellular localization of PDR-1 and alpha-Synuclein processing. Results:We show that the mCherry::pdr-1 transgene rescues the mitochondrial phenotype of pdr-1 mutants and that the expressed PDR-1 reporter is localized in the cytosol with enriched compartmentalization in the autophagy-lysosomal system. We determined that the transgenic overexpression of the PDR-1 reporter, due to inactivated small interfering RNA (siRNA) generation pathway, disrupts autophagy-lysosomal dynamics. From the RNAi screen of putative PDR-1 interactors we found that the inactivated Adenine Nucleotide Translocator ant-1.1/hANT, or hybrid ubiquitin genes ubq-2/hUBA52 and ubl-1/hRPS27A encoding a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively, induced PDR-1 abundance and affected lysosomal dynamics. In addition, we demonstrate that the abundant PDR-1 plays a role in alpha-Synuclein processing. Conclusions: These data show that the abundant C. elegans Parkin ortholog affects the autophagy-lysosomal system together with alpha-Synuclein processing which can help in understanding the pathology in Parkin-related ...

وصف الملف: text/html

العلاقة: https://doi.org/10.12688/openreseurope.14235.2Test; https://doi.org/10.12688/openreseurope.14235.1Test

الإتاحة: https://doi.org/10.12688/openreseurope.14235.1Test
https://doi.org/10.12688/openreseurope.14235.2Test

المؤلفون: Ma, Dengke, Ringstad, Niels

المصدر: Frontiers in Biology; Jun2012, Vol. 7 Issue 3, p246-253, 8p

مستخلص: Aerobic metabolism is fundamental for almost all animal life. Cellular consumption of oxygen (O) and production of carbon dioxide (CO) signal metabolic states and physiologic stresses. These respiratory gases are also detected as environmental cues that can signal external food quality and the presence of prey, predators and mates. In both contexts, animal nervous systems are endowed with mechanisms for sensing O/CO to trigger appropriate behaviors and maintain homeostasis of internal O/CO. Although different animal species show different behavioral responses to O/CO, some underlying molecular mechanisms and pathways that function in the detection of respiratory gases are fundamentally similar and evolutionarily conserved. Studies of Caenorhabditis elegans and Drosophila melanogaster have identified roles for cyclic nucleotide signaling and the hypoxia inducible factor (HIF) transcriptional pathway in mediating behavioral responses to respiratory gases. Understanding how simple invertebrate nervous systems detect respiratory gases to control behavior might reveal general principles common to nematodes, insects and vertebrates that function in the molecular sensing of respiratory gases and the neural control of animal behaviors. [ABSTRACT FROM AUTHOR]

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