BACKGROUND Hepatocellular carcinoma(HCC)is a global popular malignant tumor,which is difficult to cure,and the current treatment is limited.AIM To analyze the impacts of stress granule(SG)genes on overall survival(OS)...BACKGROUND Hepatocellular carcinoma(HCC)is a global popular malignant tumor,which is difficult to cure,and the current treatment is limited.AIM To analyze the impacts of stress granule(SG)genes on overall survival(OS),survival time,and prognosis in HCC.METHODS The combined The Cancer Genome Atlas-Liver Hepatocellular Carcinoma(TCGA-LIHC),GSE25097,and GSE36376 datasets were utilized to obtain genetic and clinical information.Optimal hub gene numbers and corresponding coefficients were determined using the Least absolute shrinkage and selection operator model approach,and genes for constructing risk scores and corresponding correlation coefficients were calculated according to multivariate Cox regression,respectively.The prognostic model’s receiver operating characteristic(ROC)curve was produced and plotted utilizing the time ROC software package.Nomogram models were constructed to predict the outcomes at 1,3,and 5-year OS prognostications with good prediction accuracy.RESULTS We identified seven SG genes(DDX1,DKC1,BICC1,HNRNPUL1,CNOT6,DYRK3,CCDC124)having a prognostic significance and developed a risk score model.The findings of Kaplan-Meier analysis indicated that the group with a high risk exhibited significantly reduced OS in comparison with those of the low-risk group(P<0.001).The nomogram model’s findings indicate a significant enhancement in the accuracy of OS prediction for individuals with HCC in the TCGA-HCC cohort.Gene Ontology and Gene Set Enrichment Analysis suggested that these SGs might be involved in the cell cycle,RNA editing,and other biological processes.CONCLUSION Based on the impact of SG genes on HCC prognosis,in the future,it will be used as a biomarker as well as a unique therapeutic target for the identification and treatment of HCC.展开更多
BACKGROUND Stress granules(SGs)could be formed under different stimulation to inhibit cell injury.AIM To investigate whether SGs could protect hepatocytes from hypoxia-induced damage during acute liver failure(ALF)by ...BACKGROUND Stress granules(SGs)could be formed under different stimulation to inhibit cell injury.AIM To investigate whether SGs could protect hepatocytes from hypoxia-induced damage during acute liver failure(ALF)by reducing endoplasmic reticulum stress(ERS)mediated apoptosis.METHODS The agonist of SGs,arsenite(Ars)was used to intervene hypoxia-induced hepatocyte injury cellular model and ALF mice models.Further,the siRNA of activating transcription factor 4(ATF4)and SGs inhibitor anisomycin was then used to intervene in cell models.RESULTS With the increase of hypoxia time from 4 h to 12 h,the levels of HIF-1α,ERS and apoptosis gradually increased,and the expression of SGs marker G3BP1 and TIA-1 was increased and then decreased.Compared with the hypoxia cell model group and ALF mice model,the levels of HIF-1α,apoptosis and ERS were increased in the Ars intervention group.After siRNA-ATF4 intervention,the level of SGs in cells increased,and the levels of HIF-1α,ERS and apoptosis decreased.Compared with the siRNA-ATF4 group,the levels of G3BP1 in the siRNAATF4+anisomycin group were decreased,and the levels of HIF-1α,ERS and apoptosis were increased.Moreover,compared with the ALF group,the degree of liver injury and liver function,the levels of HIF-1α,ERS and apoptosis in the Ars intervention group were decreased,the level of SGs was increased.CONCLUSION SGs could protect hepatocytes from hypoxia-induced damage during ALF by reducing ERSmediated apoptosis.展开更多
Abnormal expression of long interspersed element-1(LINE-1)has been implicated in drug resistance,while our previous study showed that chemotherapy drug paclitaxel(PTX)increased LINE-1 level with unknown mechanism.Bioi...Abnormal expression of long interspersed element-1(LINE-1)has been implicated in drug resistance,while our previous study showed that chemotherapy drug paclitaxel(PTX)increased LINE-1 level with unknown mechanism.Bioinformatics analysis suggested the regulation of LINE-1 mRNA by drug-induced stress granules(SGs).This study aimed to explore whether and how SGs are involved in drug-induced LINE-1 increase and thereby promotes drug resistance of triple negative breast cancer(TNBC)cells.We demonstrated that SGs increased LINE-1 expression by recruiting and stabilizing LINE-1 mRNA under drug stress,thereby adapting TNBC cells to chemotherapy drugs.Moreover,LINE-1 inhibitor efavirenz(EFV)could inhibit drug-induced SG to destabilize LINE-1.Our study provides the first evidence of the regulation of LINE-1 by SGs that could be an important survival mechanism for cancer cells exposed to chemotherapy drugs.The findings provide a useful clue for developing new chemotherapeutic strategies against TNBCs.展开更多
Stress granules(SGs)are cytoplasmic ribonucleoprotein assemblies formed under stress conditions and are related to various biological processes and human diseases.Previous studies have reported the regulatory role of ...Stress granules(SGs)are cytoplasmic ribonucleoprotein assemblies formed under stress conditions and are related to various biological processes and human diseases.Previous studies have reported the regulatory role of some proteins and linear RNAs in SG assembly.However,the relationship between circular RNAs(circRNAs)and SGs has not been discovered.Here,we screened both linear RNAs and circRNAs in SGs using improved total RNA sequencing of purified SG cores in mammalian cells and identified circular transcripts specifically localized in SGs.circRNAs with higher SG-related RNA-binding protein(RBP)binding abilities are more likely to be enriched in SGs.Furthermore,some SG-enriched circRNAs are differentially expressed in hepatocellular carcinoma(HCC)and adjacent tissues.These results suggest the regulatory role of circRNAs in SG formation and provide insights into the biological function of circRNAs and SGs in HCC.展开更多
The nucleocapsid(N)protein of SARS-CoV-2 has been reported to have a high ability of liquid-liquid phase separation,which enables its incorporation into stress granules(SGs)of host cells.However,whether SG invasion by...The nucleocapsid(N)protein of SARS-CoV-2 has been reported to have a high ability of liquid-liquid phase separation,which enables its incorporation into stress granules(SGs)of host cells.However,whether SG invasion by N protein occurs in the scenario of SARS-CoV-2 infection is unknow,neither do we know its con-sequence.Here,we used SARS-CoV-2 to infect mam-malian cells and observed the incorporation of N protein into SGs,which resulted in markedly impaired self-dis-assembly but stimulated cell cellular clearance of SGs.NMR experiments further showed that N protein binds to the SG-related amyloid proteins via non-specific tran-sient interactions,which not only expedites the phase transition of these proteins to aberrant amyloid aggre-gation in vitro,but also promotes the aggregation of FUS with ALS-associated P525L mutation in cells.In addition,we found that ACE2 is not necessary for the infection of SARS-CoV-2 to mammalian cells.Our work indicates that SARS-CoV-2 infection can impair the dis-assembly of host SGs and promote the aggregation of SG-related amyloid proteins,which may lead to an increased risk of neurodegeneration.展开更多
The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves t...The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).展开更多
Post-transcriptional methylation of N6-adenine and Nl-adenine can affect transcriptome turnover and translation.Furthermore,the regulatory function of N6-methyladenine(m6A)during heat shock has been uncovered,includin...Post-transcriptional methylation of N6-adenine and Nl-adenine can affect transcriptome turnover and translation.Furthermore,the regulatory function of N6-methyladenine(m6A)during heat shock has been uncovered,including the enhancement of the phase separation potential of RNAs.In response to acute stress,e.g.heat shock,the orderly sequestration of mRNAs in stress granules(SGs)is considered important to protect transcripts from the irreversible aggregation.Until recently,the role of N1-methyladenine(m^(1)A)on mRNAs during acute stress response remains largely unknown.Here we show that the methyltransferase complex TRMT6/61A,which generates the tag,is involved in transcriptome protection during heat shock.Our bioinformatics analysis indicates that occurrence of the motif is increased in mRNAs known to be enriched in SGs.Accordingly,the m^(1)A-generating methyltransferase TRMT6/61A accumulated in SGs and mass spectrometry confirmed enrichment of in the SG RNAs.The insertion of a single methylation motif in the untranslated region of a reporter RNA leads to more efficient recovery of protein synthesis from that transcript after the return to normal temperature.Our results demonstrate far-reaching functional consequences of a minimal RNA modification on N1-adenine during acute proteostasis stress.展开更多
Stress granules are non-membranous cytoplasmic foci induced by various stress conditions.It is a protective strategy used by cells to suppress overall translation during stress.In cancer cells,it was thought that the ...Stress granules are non-membranous cytoplasmic foci induced by various stress conditions.It is a protective strategy used by cells to suppress overall translation during stress.In cancer cells,it was thought that the formation of stress granules could protect them from apoptosis and induces resistance towards anti-cancer drugs or radiation treatment which makes the stress granules a potential target for cancer treatment.However,most of our understanding of stress granules are still in the stage of molecular and cell biology,and a transitional gap for its actual effect on clinical settings remains.In this review,we summarize the mechanism and effect of stress granules formation in cancer and try to illuminate its potential applications in cancer therapy,using breast cancer as an example.展开更多
Cytoplasmic processing bodies,termed P bodies,are involved in diverse post-transcriptional processes including mRNA decay,nonsense-mediated RNA decay(NMD),RNAi,miRNA-mediated translational repression and storage of tr...Cytoplasmic processing bodies,termed P bodies,are involved in diverse post-transcriptional processes including mRNA decay,nonsense-mediated RNA decay(NMD),RNAi,miRNA-mediated translational repression and storage of translationally silenced mRNAs.Regulation of the formation of P bodies in the context of multicellular organisms is poorly understood.Here we describe a systematic RNAi screen in C.elegans that identified 224 genes with diverse cellular functions whose inactivations result in a dramatic increase in the number of P bodies.83 of these genes form a complex functional interaction network regulating NMD.We demonstrate that NMD interfaces with many cellular processes including translation,ubiquitin-mediated protein degradation,intracellular trafficking and cytoskeleton structure.We also uncover an extensive link between translation and RNAi,with different steps in protein synthesis appearing to have distinct effects on RNAi efficiency.Moreover,the intracellular vesicular trafficking network plays an important role in the regulation of RNAi.A subset of genes enhancing P body formation also regulate the formation of stress granules in C.elegans.Our study offers insights into the cellular mechanisms that regulate the formation of P bodies and also provides a framework for system-level understanding of NMD and RNAi in the context of the development of multicellular organisms.展开更多
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to pro-gressive paralysis. Although most cases are sporadic,-10% are familial. Similar protein...Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to pro-gressive paralysis. Although most cases are sporadic,-10% are familial. Similar proteins are found in aggregates in sporadicand familial ALS, and over the last decade, research has been focused on the underlying nature of this common pathology.Notably, TDP-43 inclusions are found in almost all ALS patients, while Fus inclusions have been reported in some familial ALSpatients. Both TDP-43 and FUS possess ‘low-complexity domains' (LCDs) and are considered as ‘intrinsically disordered proteins',which form liquid droplets in vitro due to the weak interactions caused by the LCDs. Dysfunctional ‘liquid-lquid phase separa-tion'(LLPS) emerged as a new mechanism linking AlS-related proteins to pathogenesis. Here, we review the current state ofknowledge on ALS-related gene products associated with a proteinopathy and discuss their status as lLPS proteins. n addition,we highlight the therapeutic potential of targeting LLPS for treating ALS.展开更多
基金Supported by Hebei Traditional Chinese Medicine Scientific Research Project,No.2023223.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a global popular malignant tumor,which is difficult to cure,and the current treatment is limited.AIM To analyze the impacts of stress granule(SG)genes on overall survival(OS),survival time,and prognosis in HCC.METHODS The combined The Cancer Genome Atlas-Liver Hepatocellular Carcinoma(TCGA-LIHC),GSE25097,and GSE36376 datasets were utilized to obtain genetic and clinical information.Optimal hub gene numbers and corresponding coefficients were determined using the Least absolute shrinkage and selection operator model approach,and genes for constructing risk scores and corresponding correlation coefficients were calculated according to multivariate Cox regression,respectively.The prognostic model’s receiver operating characteristic(ROC)curve was produced and plotted utilizing the time ROC software package.Nomogram models were constructed to predict the outcomes at 1,3,and 5-year OS prognostications with good prediction accuracy.RESULTS We identified seven SG genes(DDX1,DKC1,BICC1,HNRNPUL1,CNOT6,DYRK3,CCDC124)having a prognostic significance and developed a risk score model.The findings of Kaplan-Meier analysis indicated that the group with a high risk exhibited significantly reduced OS in comparison with those of the low-risk group(P<0.001).The nomogram model’s findings indicate a significant enhancement in the accuracy of OS prediction for individuals with HCC in the TCGA-HCC cohort.Gene Ontology and Gene Set Enrichment Analysis suggested that these SGs might be involved in the cell cycle,RNA editing,and other biological processes.CONCLUSION Based on the impact of SG genes on HCC prognosis,in the future,it will be used as a biomarker as well as a unique therapeutic target for the identification and treatment of HCC.
基金the National Natural Science Foundation of China,No.82100630 and No.82100894the Fundamental Research Funds for the Central Universities,No.2042021kf0080.
文摘BACKGROUND Stress granules(SGs)could be formed under different stimulation to inhibit cell injury.AIM To investigate whether SGs could protect hepatocytes from hypoxia-induced damage during acute liver failure(ALF)by reducing endoplasmic reticulum stress(ERS)mediated apoptosis.METHODS The agonist of SGs,arsenite(Ars)was used to intervene hypoxia-induced hepatocyte injury cellular model and ALF mice models.Further,the siRNA of activating transcription factor 4(ATF4)and SGs inhibitor anisomycin was then used to intervene in cell models.RESULTS With the increase of hypoxia time from 4 h to 12 h,the levels of HIF-1α,ERS and apoptosis gradually increased,and the expression of SGs marker G3BP1 and TIA-1 was increased and then decreased.Compared with the hypoxia cell model group and ALF mice model,the levels of HIF-1α,apoptosis and ERS were increased in the Ars intervention group.After siRNA-ATF4 intervention,the level of SGs in cells increased,and the levels of HIF-1α,ERS and apoptosis decreased.Compared with the siRNA-ATF4 group,the levels of G3BP1 in the siRNAATF4+anisomycin group were decreased,and the levels of HIF-1α,ERS and apoptosis were increased.Moreover,compared with the ALF group,the degree of liver injury and liver function,the levels of HIF-1α,ERS and apoptosis in the Ars intervention group were decreased,the level of SGs was increased.CONCLUSION SGs could protect hepatocytes from hypoxia-induced damage during ALF by reducing ERSmediated apoptosis.
基金supported by the National Natural Science Foundation of China(Grant No.82072580 and No.81572789).
文摘Abnormal expression of long interspersed element-1(LINE-1)has been implicated in drug resistance,while our previous study showed that chemotherapy drug paclitaxel(PTX)increased LINE-1 level with unknown mechanism.Bioinformatics analysis suggested the regulation of LINE-1 mRNA by drug-induced stress granules(SGs).This study aimed to explore whether and how SGs are involved in drug-induced LINE-1 increase and thereby promotes drug resistance of triple negative breast cancer(TNBC)cells.We demonstrated that SGs increased LINE-1 expression by recruiting and stabilizing LINE-1 mRNA under drug stress,thereby adapting TNBC cells to chemotherapy drugs.Moreover,LINE-1 inhibitor efavirenz(EFV)could inhibit drug-induced SG to destabilize LINE-1.Our study provides the first evidence of the regulation of LINE-1 by SGs that could be an important survival mechanism for cancer cells exposed to chemotherapy drugs.The findings provide a useful clue for developing new chemotherapeutic strategies against TNBCs.
基金supported by grants from the National Key R&D Program of China(Grant Nos.2021YFA1300500 and 2021YFA1302000)the National Natural Science Foundation of China(Grant Nos.32130020,32025009,and 91940306).
文摘Stress granules(SGs)are cytoplasmic ribonucleoprotein assemblies formed under stress conditions and are related to various biological processes and human diseases.Previous studies have reported the regulatory role of some proteins and linear RNAs in SG assembly.However,the relationship between circular RNAs(circRNAs)and SGs has not been discovered.Here,we screened both linear RNAs and circRNAs in SGs using improved total RNA sequencing of purified SG cores in mammalian cells and identified circular transcripts specifically localized in SGs.circRNAs with higher SG-related RNA-binding protein(RBP)binding abilities are more likely to be enriched in SGs.Furthermore,some SG-enriched circRNAs are differentially expressed in hepatocellular carcinoma(HCC)and adjacent tissues.These results suggest the regulatory role of circRNAs in SG formation and provide insights into the biological function of circRNAs and SGs in HCC.
基金This work was supported by the National Natural Science Foundation(NSF)of China(32170683,82188101,32171236,31872716,32070049,82041016)the Major State Basic Research Development Program(2019YFE0120600)+5 种基金the Science and Technology Commission of Shanghai Municipality(STCSM)(20XD1425000 and 2019SHZDZX02)CAS project for Young Scientists in Basic research(YSBR-009)the Eastem Scholar project supported by Shanghai Municipal Education Commission,National Key R&D Program of China(2021YFC2301700,2021YFA1301900)Yunnan Key Research and Development project(202103AQ100001)CAMS Innovation Fund for Medical Sciences(2021-12M-1-038)special research fund on COVID-19 of Sichuan Province(2020YFS0010).
文摘The nucleocapsid(N)protein of SARS-CoV-2 has been reported to have a high ability of liquid-liquid phase separation,which enables its incorporation into stress granules(SGs)of host cells.However,whether SG invasion by N protein occurs in the scenario of SARS-CoV-2 infection is unknow,neither do we know its con-sequence.Here,we used SARS-CoV-2 to infect mam-malian cells and observed the incorporation of N protein into SGs,which resulted in markedly impaired self-dis-assembly but stimulated cell cellular clearance of SGs.NMR experiments further showed that N protein binds to the SG-related amyloid proteins via non-specific tran-sient interactions,which not only expedites the phase transition of these proteins to aberrant amyloid aggre-gation in vitro,but also promotes the aggregation of FUS with ALS-associated P525L mutation in cells.In addition,we found that ACE2 is not necessary for the infection of SARS-CoV-2 to mammalian cells.Our work indicates that SARS-CoV-2 infection can impair the dis-assembly of host SGs and promote the aggregation of SG-related amyloid proteins,which may lead to an increased risk of neurodegeneration.
基金in part supported by the National Natural Science Foundation of China,Nos.30560042,81160161,81360198,and 82160255Education Department of Jiangxi Province,Nos.GJJ13198 and GJJ170021+1 种基金Jiangxi Provincial Department of Science and Technology,No.20192BAB205043Health and Family Planning Commission of Jiangxi Province,Nos.20181019 and 202210002(all to RX)。
文摘The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).
基金This work was funded by the European Research Council grants MetaMeta_311522(R.M.V.)RIBOMYLOME_309545(G.G.T.)+5 种基金ASTRA_855923(G.G.T)G.G.T.acknowledges support of the H2020 projects IASIS_727658 and INFORE_825080the Spanish Ministry of Economy and Competitiveness BFU2017-86970-Pas well as the collaboration with Peter St.George-Hyslop financed by the Wellcome TrustR.M.V.acknowledges support by the Deutsche Forschungsgemeinschaft(DFG)grant EXC115M.H.is funded by DFG CRC902‘Molecular Principles of RNA-based Regulation’。
文摘Post-transcriptional methylation of N6-adenine and Nl-adenine can affect transcriptome turnover and translation.Furthermore,the regulatory function of N6-methyladenine(m6A)during heat shock has been uncovered,including the enhancement of the phase separation potential of RNAs.In response to acute stress,e.g.heat shock,the orderly sequestration of mRNAs in stress granules(SGs)is considered important to protect transcripts from the irreversible aggregation.Until recently,the role of N1-methyladenine(m^(1)A)on mRNAs during acute stress response remains largely unknown.Here we show that the methyltransferase complex TRMT6/61A,which generates the tag,is involved in transcriptome protection during heat shock.Our bioinformatics analysis indicates that occurrence of the motif is increased in mRNAs known to be enriched in SGs.Accordingly,the m^(1)A-generating methyltransferase TRMT6/61A accumulated in SGs and mass spectrometry confirmed enrichment of in the SG RNAs.The insertion of a single methylation motif in the untranslated region of a reporter RNA leads to more efficient recovery of protein synthesis from that transcript after the return to normal temperature.Our results demonstrate far-reaching functional consequences of a minimal RNA modification on N1-adenine during acute proteostasis stress.
基金This work was supported by the National Natural Science Foundation of China(No.82002979 and 81702839)the Scientific Research and Development Funds of Peking Uni・versity People's Hospital,China(No.RDY2020-16).
文摘Stress granules are non-membranous cytoplasmic foci induced by various stress conditions.It is a protective strategy used by cells to suppress overall translation during stress.In cancer cells,it was thought that the formation of stress granules could protect them from apoptosis and induces resistance towards anti-cancer drugs or radiation treatment which makes the stress granules a potential target for cancer treatment.However,most of our understanding of stress granules are still in the stage of molecular and cell biology,and a transitional gap for its actual effect on clinical settings remains.In this review,we summarize the mechanism and effect of stress granules formation in cancer and try to illuminate its potential applications in cancer therapy,using breast cancer as an example.
基金by the National High Technology Research and Development Program of China(863 Program)(Grant No.2005AA210910).
文摘Cytoplasmic processing bodies,termed P bodies,are involved in diverse post-transcriptional processes including mRNA decay,nonsense-mediated RNA decay(NMD),RNAi,miRNA-mediated translational repression and storage of translationally silenced mRNAs.Regulation of the formation of P bodies in the context of multicellular organisms is poorly understood.Here we describe a systematic RNAi screen in C.elegans that identified 224 genes with diverse cellular functions whose inactivations result in a dramatic increase in the number of P bodies.83 of these genes form a complex functional interaction network regulating NMD.We demonstrate that NMD interfaces with many cellular processes including translation,ubiquitin-mediated protein degradation,intracellular trafficking and cytoskeleton structure.We also uncover an extensive link between translation and RNAi,with different steps in protein synthesis appearing to have distinct effects on RNAi efficiency.Moreover,the intracellular vesicular trafficking network plays an important role in the regulation of RNAi.A subset of genes enhancing P body formation also regulate the formation of stress granules in C.elegans.Our study offers insights into the cellular mechanisms that regulate the formation of P bodies and also provides a framework for system-level understanding of NMD and RNAi in the context of the development of multicellular organisms.
基金Research of the authors is supported by VIB,KU Leuven(Cl and‘Opening the Future’Fund),the‘Fund for Scientific Research Flanders'(FWO-Vlaandere n),the Agency for Irmovation by Science and Technology in Flanders,the Thierry Latran Foundation,the*Association Beige contre les Maladies n euro-Musculaires,(AB MM),the Muscular Dystrophy Association(MDA),Target ALS,the ALS Liga Belgie(A Cure for ALS),and the ALS Association(ALSA).D.P.is funded by the VIB International Life Sciences PhD Program.V.B.is supported by a postdoctoral fellowship from the FWO-Vlaanderen.G.O.ack no wledges funding by the Research Foundation Flan ders(FWO)—project nr.G.0328.16N.
文摘Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to pro-gressive paralysis. Although most cases are sporadic,-10% are familial. Similar proteins are found in aggregates in sporadicand familial ALS, and over the last decade, research has been focused on the underlying nature of this common pathology.Notably, TDP-43 inclusions are found in almost all ALS patients, while Fus inclusions have been reported in some familial ALSpatients. Both TDP-43 and FUS possess ‘low-complexity domains' (LCDs) and are considered as ‘intrinsically disordered proteins',which form liquid droplets in vitro due to the weak interactions caused by the LCDs. Dysfunctional ‘liquid-lquid phase separa-tion'(LLPS) emerged as a new mechanism linking AlS-related proteins to pathogenesis. Here, we review the current state ofknowledge on ALS-related gene products associated with a proteinopathy and discuss their status as lLPS proteins. n addition,we highlight the therapeutic potential of targeting LLPS for treating ALS.