Diabetes involves multi-organ complications that seriously threaten human life and health,and has become a major public health problem of global concern.Unfortunately,clinical management strategies for diabetic compli...Diabetes involves multi-organ complications that seriously threaten human life and health,and has become a major public health problem of global concern.Unfortunately,clinical management strategies for diabetic complications are still in their“infancy”,restricted by a limited understanding of their complex pathological mechanism.As is well established,lipid metabolism disorder is the characteristic pathological factors of diabetes,but the detailed molecular mechanisms driving the progression of multi-organ complications remain obscure.Protein S-acylation(often referred to as S-palmitoylation)is a reversible lipid modification that reversibly binds fatty acids to protein-specific cysteine(Cys)residues through palmitoyl acyl transferases(PATs,also known as DHHCs)and deacylation enzymes,which is involved in the pathological progression of a variety of complex diseases such as cancer,neurological disorders and metabolic syndrome.Notably,recent studies have shown that protein S-acylation drives the progression of diabetes and its multiple complications,and targeted intervention in the protein S-acylation process significantly alleviates the progression of diabetes and its complications,suggesting that protein S-acylation may be a common pathological link and intervention target of diabetes complications.Therefore,this review systematically comprehends the contribution of protein S-acylation to the progression of diabetes and its complications,summarizes the influence of the diabetic environment on S-acylation related enzymes,as well as providing an in-depth analysis of current drugs,measures,and challenges in targeting S-acylation.Finally,the accessibility of targeting protein S-acylation to prevent diabetes and its complications and the focus of future in-depth studies are envisioned,with a view to providing comprehensive and in-depth references and rationale for future novel strategies targeting protein S-acylation to prevent and treat diabetes and its multi-organ complications.展开更多
Hetero-tetrameric soluble N-ethylmaleimide-sensitive factor attachment protein receptors(SNAREs)complexes are critical for vesicle-target membrane fusion within the endomembrane system of eukaryotic cells.SNARE assemb...Hetero-tetrameric soluble N-ethylmaleimide-sensitive factor attachment protein receptors(SNAREs)complexes are critical for vesicle-target membrane fusion within the endomembrane system of eukaryotic cells.SNARE assembly involves four different SNARE motifs,Qa,Qb,Qc,and R,providedby three orfour SNARE proteins.YKT6 is an atypical R-SNARE that lacks a transmembrane domain and is involved in multiple vesicle-target membrane fusions.Although YKT6 is evolutionarily conserved and essential,its function and regulation in different phyla seem distinct.Arabidopsis YKT61,the yeast and metazoan YKT6 homologue,is essential for gametophytic development,plays a critical role in sporophytic cells,and me-diates multiple vesicle-target membrane fusion.However,its molecular regulation is unclear.We report here that YKT61 is S-acylated.Abolishing its S-acylation by a C195S mutation dissociates YKT61 from endomembrane structures and causes its functional loss.Although interacting with various SNARE pro-teins,YKT61functions not as a canonical R-SNAREbut coordinates with otherR-SNAREs to participate in theformationof SNAREcomplexes.Phylum-specific molecular regulation of YKT6 may be evolvedto allow more efficient SNARE assembly in different eukaryotic cells.展开更多
Plants have developed a multi-layered immune system to cope with pathogens.The receptors on the plasma membrane are controlled by endocytosis to modulate immune signaling,but the regulatory mechanisms of endocytosis i...Plants have developed a multi-layered immune system to cope with pathogens.The receptors on the plasma membrane are controlled by endocytosis to modulate immune signaling,but the regulatory mechanisms of endocytosis in this process remain largely unclear.Here,we uncover that reversible S-acylation of BONZAl1(BON1),a conserved copine-family protein that regulates development-immunity balance in Arabidopsis,contributes to the accurate control of endocytosis.BON1 is targeted by S-acylation,a type of protein lipidation,for its localization on the plasma membrane and its function in development and immunity.Furthermore,the S-acylation status of BON1affects its association with the light-chain clathrin subunitCLC3 and regulates endocytosis.Specifically,PAT14 facilitates the S-acylation of BON1,while ABAPT11 mediates its de-S-acylation.Physiological levels of reversible S-acylation of BON1 are essential for endocytosis and the internalization of immune receptors.Interestingly,salicylic acid enhances ABAPT11-dependent de-S-acylation of BON1 to amplify immune signaling.Collectively,our study reveals that reversible S-acylation of BON1 precisely regulates immune receptor internalization for balancing plant development and immunity,providing potential targets that may be used to improve crop yields and disease resistance.展开更多
Geminiviruses are an important group of viruses that infect a variety of plants and result in heavy agricultural losses worldwide.The homologs of C4(or L4)in monopartite geminiviruses and AC4(or AL4)in bipartite gemin...Geminiviruses are an important group of viruses that infect a variety of plants and result in heavy agricultural losses worldwide.The homologs of C4(or L4)in monopartite geminiviruses and AC4(or AL4)in bipartite geminiviruses are critical viral proteins.The C4 proteins from several geminiviruses are the substrates of S-acylation,a dynamic posttranslational modification,for the maintenance of their membrane localization and function in virus infection.Here we initiated a screening and identified a plant protein ABAPT3(Alpha/Beta Hydrolase Domain-containing Protein 17-like Acyl Protein Thioesterase 3)as the de-S-acylation enzyme of C4 encoded by BSCTV(Beet severe curly top virus).Overexpression of ABAPT3 reduced the S-acylation of BSCTV C4,disrupted its plasma membrane localization,inhibited its function in pathogenesis,and suppressed BSCTV infection.Because the S-acylation motifs are conserved among C4 from different geminiviruses,we tested the effect of ABAPT3 on the C4 protein of ToLCGdV(Tomato leaf curl Guangdong virus)from another geminivirus genus.Consistently,ABAPT3 overexpression also disrupted the S-acylation,subcellular localization,and function of ToLCGdV C4,and inhibited ToLCGdV infection.In summary,we provided a new approach to globally improve the resistance to different types of geminiviruses in plants via de-Sacylation of the viral C4 proteins and it can be extendedly used for suppression of geminivirus infection in crops.展开更多
Remorins are plant-specific membrane-associated proteins and were proposed to play crucial roles in plant-pathogen interactions. However, little is known about how pathogens counter remorin-mediated host responses. In...Remorins are plant-specific membrane-associated proteins and were proposed to play crucial roles in plant-pathogen interactions. However, little is known about how pathogens counter remorin-mediated host responses. In this study, by quantitative whole-proteome analysis we found that the remorin protein （NbREM1） is downregulated early in Rice stripe virus （RSV） infection. We further discovered that the turn- over of NbREM1 is regulated by S-acylation modification and its degradation is mediated mainly through the autophagy pathway. Interestingly, RSV can interfere with the S-acylation of NbREM1, which is required to negatively regulate RSV infection by restricting virus cell-to-cell trafficking. The disruption of NbREM1 S-acylation affects its targeting to the plasma membrane microdomain, and the resulting accumulation of non-targeted NbREM1 is subjected to autophagic degradation, causing downregulation of NbREMI. Moreover, we found that RSV-encoded movement protein, NSvc4, alone can interfere with NbREM1 S-acylation through binding with the C-terminal domain of NbREM1 the S-acylation of OsREM1.4, the homologous remorin of NbREM1, and thus remorin-mediated defense against RSV in rice, the original host of RSV, indicating that downregulation of the remorin protein level by interfering with its S-acylation is a common strategy adopted by RSV to overcome remorin-mediated inhibition of virus movement.展开更多
Nucleotide binding,leucine-rich repeat(NB-LRR)proteins are critical for disease resistance in plants,while we do not know whether S-acylation of these proteins plays a role during bacterial infection.We identified 30 ...Nucleotide binding,leucine-rich repeat(NB-LRR)proteins are critical for disease resistance in plants,while we do not know whether S-acylation of these proteins plays a role during bacterial infection.We identified 30 Arabidopsis mutants with mutations in NB-LRR encoding genes from the Nottingham Arabidopsis Stock Center and characterized their contribution to the plant immune response after inoculation with Pseudomonas syringae pv tomato DC3000(Pst DC3000).Of the five mutants that were hyper-susceptible to the pathogen,three(R5L1,R5L2 and RPS5)proteins contain the conserved S-acylation site in the N-terminal coiled-coil(CC)domain.In wild-type(WT)Arabidopsis plants,R5L1 was transcriptionally activated upon pathogen infection,and R5L1 overexpression lines had enhanced resistance.Independent experiments indicated that R5L1 localized at the plasma membrane(PM)via S-acylation of its N-terminal CC domain,which was mediated by PROTEIN S-ACYL TRANSFERASE 13/16(PAT13,PAT16).Modification of the S-acylation site reduced its affinity for binding the PM,with a consequent significant reduction in bacterial resistance.PM localization of R5L1 was significantly reduced in pat13 and pat16 mutants,similar to what was found for WT plants treated with 2-bromopalmitate,an S-acylationblocking agent.Transgenic plants expressing R5L1 in the pat13 pat16 double mutant showed no enhanced disease resistance.Overexpression of R5L1 in WT Arabidopsis resulted in substantial accumulation of reactive oxygen species after inoculation with Pst DC3000;this effect was not observed with a mutant R5L1 carrying a mutated Sacylation site.Our data suggest that PAT13-and PAT16-mediated S-acylation of R5L1 is crucial for its membrane localization to activate the plant defense response.展开更多
Alterations in cellular calcium(Ca^(2+))signals have been causally associated with the development and progression of human cancers.Cellular Ca^(2+)signals are generated by channels,pumps,and exchangers that move Ca^(...Alterations in cellular calcium(Ca^(2+))signals have been causally associated with the development and progression of human cancers.Cellular Ca^(2+)signals are generated by channels,pumps,and exchangers that move Ca^(2+)ions across membranes and are decoded by effector proteins in the cytosol or in organelles.S-acylation,the reversible addition of 16-carbon fatty acids to proteins,modulates the activity of Ca^(2+)transporters by altering their affinity for lipids,and enzymes mediating this reversible post-translational modification have also been linked to several types of cancers.Here,we compile studies reporting an association between Ca^(2+)transporters or S-acylation enzymes with specific cancers,as well as studies reporting or predicting the S-acylation of Ca^(2+)transporters.We then discuss the potential role of S-acylation in the oncogenic potential of a subset of Ca^(2+)transport proteins involved in cancer.展开更多
Abiotic stresses,particularly salinity,pose a major threat to rice productivity,highlighting the need to identify novel genetic resources to improve stress tolerance.Gamma irradiation remains one of the most widely us...Abiotic stresses,particularly salinity,pose a major threat to rice productivity,highlighting the need to identify novel genetic resources to improve stress tolerance.Gamma irradiation remains one of the most widely used tools breeding stress-tolerant plant varieties.In this study,we identified a salt-tolerant rice mutant,salt-insensitive TILLING line 4(sitl4),generated via gamma irradiation and linked its enhanced tolerance to a loss-of-function mutation in Oryza sativa protein acyltransferase for ABA response 1(OsPATA1),which encodes a DHHC-type palmitoyl acyltransferase.Functional analyses using both sitl4 and a CRISPR/Cas9-mediated OsPATA1-knockout line(ospata1)revealed that disruption of OsPATA1 leads to increased abscisic acid(ABA)accumulation and upregulation of ABA-responsive genes under salt stress conditions.We identified OsEULD1b,a previously uncharacterized Euonymus lectin(EUL)domaincontaining protein,as an interactor of OsPATA1.In sitl4 and ospata1,OsEULD1b displayed cytosolic retention,suggesting that its subcellular redistribution enhances its role in ABA-mediated stress signaling.Taken together,our findings demonstrate that OsPATA1 and OsEULD1b form a regulatory module that modulates the ABA-dependent salt stress responses in rice.These results provide new insights into the molecular mechanisms underlying abiotic stress tolerance and will help to identify potential genetic targets for developing stress-tolerant rice cultivars through molecular breeding or genome editing.展开更多
基金supported by National Natural Science Foundation of China(No.82304909)National Natural Science Foundation of China(No.82174112)Tianjin Science and Technology Innovation Base Construction(No.24ZYJDSY00280).
文摘Diabetes involves multi-organ complications that seriously threaten human life and health,and has become a major public health problem of global concern.Unfortunately,clinical management strategies for diabetic complications are still in their“infancy”,restricted by a limited understanding of their complex pathological mechanism.As is well established,lipid metabolism disorder is the characteristic pathological factors of diabetes,but the detailed molecular mechanisms driving the progression of multi-organ complications remain obscure.Protein S-acylation(often referred to as S-palmitoylation)is a reversible lipid modification that reversibly binds fatty acids to protein-specific cysteine(Cys)residues through palmitoyl acyl transferases(PATs,also known as DHHCs)and deacylation enzymes,which is involved in the pathological progression of a variety of complex diseases such as cancer,neurological disorders and metabolic syndrome.Notably,recent studies have shown that protein S-acylation drives the progression of diabetes and its multiple complications,and targeted intervention in the protein S-acylation process significantly alleviates the progression of diabetes and its complications,suggesting that protein S-acylation may be a common pathological link and intervention target of diabetes complications.Therefore,this review systematically comprehends the contribution of protein S-acylation to the progression of diabetes and its complications,summarizes the influence of the diabetic environment on S-acylation related enzymes,as well as providing an in-depth analysis of current drugs,measures,and challenges in targeting S-acylation.Finally,the accessibility of targeting protein S-acylation to prevent diabetes and its complications and the focus of future in-depth studies are envisioned,with a view to providing comprehensive and in-depth references and rationale for future novel strategies targeting protein S-acylation to prevent and treat diabetes and its multi-organ complications.
基金This work is supported by National Natural Science Foundation of China(31970332).
文摘Hetero-tetrameric soluble N-ethylmaleimide-sensitive factor attachment protein receptors(SNAREs)complexes are critical for vesicle-target membrane fusion within the endomembrane system of eukaryotic cells.SNARE assembly involves four different SNARE motifs,Qa,Qb,Qc,and R,providedby three orfour SNARE proteins.YKT6 is an atypical R-SNARE that lacks a transmembrane domain and is involved in multiple vesicle-target membrane fusions.Although YKT6 is evolutionarily conserved and essential,its function and regulation in different phyla seem distinct.Arabidopsis YKT61,the yeast and metazoan YKT6 homologue,is essential for gametophytic development,plays a critical role in sporophytic cells,and me-diates multiple vesicle-target membrane fusion.However,its molecular regulation is unclear.We report here that YKT61 is S-acylated.Abolishing its S-acylation by a C195S mutation dissociates YKT61 from endomembrane structures and causes its functional loss.Although interacting with various SNARE pro-teins,YKT61functions not as a canonical R-SNAREbut coordinates with otherR-SNAREs to participate in theformationof SNAREcomplexes.Phylum-specific molecular regulation of YKT6 may be evolvedto allow more efficient SNARE assembly in different eukaryotic cells.
基金supported by National Natural Science Foundation of China(32270752,32270292,and 32400227)Major Program of Guangdong Basic and Applied Research(2019B030302006)+3 种基金Natural Science Foundation of Guangdong,China(2024A1515011071 and 2023A1515110948)Guangdong Modern Agro-industry Technology Research System(2023KJ114)the Program for Changjiang Scholars,the China Post doctoral Science Foundation(2023M741236)the Postdoctoral Fellowship Program of CPSF(GZB20240238).
文摘Plants have developed a multi-layered immune system to cope with pathogens.The receptors on the plasma membrane are controlled by endocytosis to modulate immune signaling,but the regulatory mechanisms of endocytosis in this process remain largely unclear.Here,we uncover that reversible S-acylation of BONZAl1(BON1),a conserved copine-family protein that regulates development-immunity balance in Arabidopsis,contributes to the accurate control of endocytosis.BON1 is targeted by S-acylation,a type of protein lipidation,for its localization on the plasma membrane and its function in development and immunity.Furthermore,the S-acylation status of BON1affects its association with the light-chain clathrin subunitCLC3 and regulates endocytosis.Specifically,PAT14 facilitates the S-acylation of BON1,while ABAPT11 mediates its de-S-acylation.Physiological levels of reversible S-acylation of BON1 are essential for endocytosis and the internalization of immune receptors.Interestingly,salicylic acid enhances ABAPT11-dependent de-S-acylation of BON1 to amplify immune signaling.Collectively,our study reveals that reversible S-acylation of BON1 precisely regulates immune receptor internalization for balancing plant development and immunity,providing potential targets that may be used to improve crop yields and disease resistance.
基金supported by the Major Program of Guangdong Basic and Applied Research(2019B030302006)National Natural Science Foundation of China(32270752,31970531,32270292,32272509)+2 种基金Natural Science Foundation of Guangdong(2024A1515011071,2021A1515011151,2019A1515110330)Guangdong Modern Agro-industry Technology Research System(2023KJ114)the Program for Changjiang Scholars,and the Guangdong Special Support Program of Young Top-Notch Talent in Science and Technology Innovation(2019TQ05N651).
文摘Geminiviruses are an important group of viruses that infect a variety of plants and result in heavy agricultural losses worldwide.The homologs of C4(or L4)in monopartite geminiviruses and AC4(or AL4)in bipartite geminiviruses are critical viral proteins.The C4 proteins from several geminiviruses are the substrates of S-acylation,a dynamic posttranslational modification,for the maintenance of their membrane localization and function in virus infection.Here we initiated a screening and identified a plant protein ABAPT3(Alpha/Beta Hydrolase Domain-containing Protein 17-like Acyl Protein Thioesterase 3)as the de-S-acylation enzyme of C4 encoded by BSCTV(Beet severe curly top virus).Overexpression of ABAPT3 reduced the S-acylation of BSCTV C4,disrupted its plasma membrane localization,inhibited its function in pathogenesis,and suppressed BSCTV infection.Because the S-acylation motifs are conserved among C4 from different geminiviruses,we tested the effect of ABAPT3 on the C4 protein of ToLCGdV(Tomato leaf curl Guangdong virus)from another geminivirus genus.Consistently,ABAPT3 overexpression also disrupted the S-acylation,subcellular localization,and function of ToLCGdV C4,and inhibited ToLCGdV infection.In summary,we provided a new approach to globally improve the resistance to different types of geminiviruses in plants via de-Sacylation of the viral C4 proteins and it can be extendedly used for suppression of geminivirus infection in crops.
文摘Remorins are plant-specific membrane-associated proteins and were proposed to play crucial roles in plant-pathogen interactions. However, little is known about how pathogens counter remorin-mediated host responses. In this study, by quantitative whole-proteome analysis we found that the remorin protein （NbREM1） is downregulated early in Rice stripe virus （RSV） infection. We further discovered that the turn- over of NbREM1 is regulated by S-acylation modification and its degradation is mediated mainly through the autophagy pathway. Interestingly, RSV can interfere with the S-acylation of NbREM1, which is required to negatively regulate RSV infection by restricting virus cell-to-cell trafficking. The disruption of NbREM1 S-acylation affects its targeting to the plasma membrane microdomain, and the resulting accumulation of non-targeted NbREM1 is subjected to autophagic degradation, causing downregulation of NbREMI. Moreover, we found that RSV-encoded movement protein, NSvc4, alone can interfere with NbREM1 S-acylation through binding with the C-terminal domain of NbREM1 the S-acylation of OsREM1.4, the homologous remorin of NbREM1, and thus remorin-mediated defense against RSV in rice, the original host of RSV, indicating that downregulation of the remorin protein level by interfering with its S-acylation is a common strategy adopted by RSV to overcome remorin-mediated inhibition of virus movement.
基金supported by grants from the National Natural Science Foundation of China(31830057 and 31690091 to Y.-X.Z.)the National Postdoctoral Program for Innovative Talent(BX20200008 to G.H.)。
文摘Nucleotide binding,leucine-rich repeat(NB-LRR)proteins are critical for disease resistance in plants,while we do not know whether S-acylation of these proteins plays a role during bacterial infection.We identified 30 Arabidopsis mutants with mutations in NB-LRR encoding genes from the Nottingham Arabidopsis Stock Center and characterized their contribution to the plant immune response after inoculation with Pseudomonas syringae pv tomato DC3000(Pst DC3000).Of the five mutants that were hyper-susceptible to the pathogen,three(R5L1,R5L2 and RPS5)proteins contain the conserved S-acylation site in the N-terminal coiled-coil(CC)domain.In wild-type(WT)Arabidopsis plants,R5L1 was transcriptionally activated upon pathogen infection,and R5L1 overexpression lines had enhanced resistance.Independent experiments indicated that R5L1 localized at the plasma membrane(PM)via S-acylation of its N-terminal CC domain,which was mediated by PROTEIN S-ACYL TRANSFERASE 13/16(PAT13,PAT16).Modification of the S-acylation site reduced its affinity for binding the PM,with a consequent significant reduction in bacterial resistance.PM localization of R5L1 was significantly reduced in pat13 and pat16 mutants,similar to what was found for WT plants treated with 2-bromopalmitate,an S-acylationblocking agent.Transgenic plants expressing R5L1 in the pat13 pat16 double mutant showed no enhanced disease resistance.Overexpression of R5L1 in WT Arabidopsis resulted in substantial accumulation of reactive oxygen species after inoculation with Pst DC3000;this effect was not observed with a mutant R5L1 carrying a mutated Sacylation site.Our data suggest that PAT13-and PAT16-mediated S-acylation of R5L1 is crucial for its membrane localization to activate the plant defense response.
基金Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung(Grant/Award Number:310030_189042)。
文摘Alterations in cellular calcium(Ca^(2+))signals have been causally associated with the development and progression of human cancers.Cellular Ca^(2+)signals are generated by channels,pumps,and exchangers that move Ca^(2+)ions across membranes and are decoded by effector proteins in the cytosol or in organelles.S-acylation,the reversible addition of 16-carbon fatty acids to proteins,modulates the activity of Ca^(2+)transporters by altering their affinity for lipids,and enzymes mediating this reversible post-translational modification have also been linked to several types of cancers.Here,we compile studies reporting an association between Ca^(2+)transporters or S-acylation enzymes with specific cancers,as well as studies reporting or predicting the S-acylation of Ca^(2+)transporters.We then discuss the potential role of S-acylation in the oncogenic potential of a subset of Ca^(2+)transport proteins involved in cancer.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)Ministry of Education(RS-2021-NR060130,00355529).
文摘Abiotic stresses,particularly salinity,pose a major threat to rice productivity,highlighting the need to identify novel genetic resources to improve stress tolerance.Gamma irradiation remains one of the most widely used tools breeding stress-tolerant plant varieties.In this study,we identified a salt-tolerant rice mutant,salt-insensitive TILLING line 4(sitl4),generated via gamma irradiation and linked its enhanced tolerance to a loss-of-function mutation in Oryza sativa protein acyltransferase for ABA response 1(OsPATA1),which encodes a DHHC-type palmitoyl acyltransferase.Functional analyses using both sitl4 and a CRISPR/Cas9-mediated OsPATA1-knockout line(ospata1)revealed that disruption of OsPATA1 leads to increased abscisic acid(ABA)accumulation and upregulation of ABA-responsive genes under salt stress conditions.We identified OsEULD1b,a previously uncharacterized Euonymus lectin(EUL)domaincontaining protein,as an interactor of OsPATA1.In sitl4 and ospata1,OsEULD1b displayed cytosolic retention,suggesting that its subcellular redistribution enhances its role in ABA-mediated stress signaling.Taken together,our findings demonstrate that OsPATA1 and OsEULD1b form a regulatory module that modulates the ABA-dependent salt stress responses in rice.These results provide new insights into the molecular mechanisms underlying abiotic stress tolerance and will help to identify potential genetic targets for developing stress-tolerant rice cultivars through molecular breeding or genome editing.
