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TERC suppresses PD-L1 expression by downregulating RNA binding protein HuR

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Science China(Life Sciences) 2022年第12期65卷 2505-2516页

作者： Heping Jin Yanlian Chen Jian Ren Junjiu Huang Yong Zhao Haiying Liu moe key laboratory of gene function and regulation School of Life SciencesSun Yat-sen UniversityGuangzhou 510006China

TERC is the RNA component of telomerase,and provides a template for TERT to synthesize telomere repeats at chromosome *** evidence has revealed that TERC is involved in other biological processes beyond ***,we found that the expression level of TERC is negatively correlated with PD-L1 and that ectopic expression of TERC but not TERT in ALT cells significantly inhibits PD-L1,suggesting that TERC suppresses PD-L1 expression in a telomerase-independent ***,instead of regulating PD-L1 m RNA directly,TERC accelerates PD-L1 m RNA degradation by inhibiting the expression of Hu R,which binds to the 3′UTR of PD-L1 m RNA and maintains its *** also found that the small molecule AS1842856,a Fox O1 inhibitor,promotes TERC expression and reverses the PD-L1 upregulation caused by chemotherapy,providing a potential combination cancer therapy that avoids cancer immune escape during chemotherapy.

关键词： TERC PD-L1 HuR FoxO1 inhibitor

Sequence-and structure-selective m RNA m5C methylation by NSUN6 in animals

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National Science Review 2021年第6期8卷 136-147页

作者： Jianheng Liu Tao Huang Yusen Zhang Tianxuan Zhao Xueni Zhao Wanying Chen Rui Zhang moe key laboratory of gene function and regulation State Key Laboratory of BiocontrolSchool of Life SciencesRNA Biomedical InstituteSun Yat-Sen Memorial HospitalSun Yat-Sen University

mRNA m5C,which has recently been implicated in the regulation of mRNA mobility,metabolism and translation,plays important regulatory roles in various biological *** types of m5C sites are found in *** Ⅰ m5C sites,which contain a downstream G-rich triplet motif and are computationally predicted to be located at the 5' end of putative hairpin structures,are methylated by *** Ⅱ m5C sites contain a downstream UCCA motif and are computationally predicted to be located in the loops of putative hairpin ***,their biogenesis remains *** we identified NSUN6,a methyltransferase that is known to methylate C72 of tRNAThrand tRNACys,as an mRNA methyltransferase that targets Type Ⅱ m5C *** the RNA secondary structure prediction,miCLIP,and results from a high-throughput mutagenesis analysis,we determined the RNA sequence and structural features governing the specificity of NSUN6-mediated mRNA *** these features into an NSUN6-RNA structural model,we identified an NSUN6 variant that largely loses tRNA methylation but retains mRNA methylation ***,we revealed a weak negative correlation between m5C methylation and translation *** findings uncover that mRNA m5C is tightly controlled by an elaborate two-enzyme system,and the protein-RNA structure analysis strategy established maybe applied to other RNA modification writers to distinguish the functions of different RNA substrates of a writer protein.

关键词： mRNAm5C NSUN6 RNA modification protein-RNA complex structure

Igniting autophagy through the regulation of phase separation

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1911-1912页

作者： Shouheng Jin Jun Cui moe key laboratory of gene function and regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen University510275 GuangzhouGuangdongChina

A recent paper published in Nature by Fujioka et *** that the Atg1(also known as ULK1 in mammals)complex undergoes phase separation to form a liquid-like biomolecular condensate,thereby promoting the formation of a preautophagosomal structure(PAS)to activate autophagy in yeast.1 This research discovered the details of a mechanism of phase separation underlying autophagy initiation and provided a better understanding of the biological condensates.

关键词： separation phase details

Engineering plants to secrete affinity-tagged pathogen elicitors for deciphering immune receptor complex or inducing enhanced immunity

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Journal of Integrative Plant Biology 2020年第6期62卷 761-776页

作者： Shuang Miao Jiuer Liu Jianhang Guo Jian-Feng Li Guangdong Provincial key laboratory of Plant Resources State Key Laboratory of BiocontrolMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China

Plant cells mount plenty of pattern-recognition receptors(PRRs)to detect the microbe-associated molecular patterns(MAMPs)from potential microbial *** are overrepresented by proteinaneous patterns,such as the flg22 peptide from bacterial *** of PRR receptor complex components by forward or reverse genetics can be time/labor-consuming,and be confounded by functional ***,we present a strategy for identifying PRR complex components by engineering plants to inducibly secrete affinity-tagged proteinaneous MAMPs to the *** PRR protein complexes bound to self-secreted MAMPs are enriched through affinity purification and dissected by mass *** a proof of principle,we could capture the flg22 receptor FLS2 and co-receptor BAK1 using Arabidopsis plants secreting FLAG-tagged flg22 under ***,we identified receptor-like kinases LIK1 and PEPR1/PEPR2 as potential components in the FLS2 receptor complex,which were further validated by protein–protein interaction assays and the reverse genetics *** study showcases a simple way to biochemically identify endogenous PRR complex components without overexpressing the PRR or using chemical crosslinkers,and suggests a possible crosstalk between different immune receptors in plants.A modest dose of estradiol can also be applied to inducing enhanced immunity in engineered plants to both bacterial and fungal pathogens.

关键词： immunity complex mount

Type-ll Metacaspases Mediate the processing of Plant Elicitor Peptides in Arabidopsis

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Molecular Plant 2019年第11期12卷 1524-1533页

作者： Wenzhong Shen Jiuer Liu Jian-Feng Li State key laboratory of Biocontrol Guangdong Provincial Key Laboratory of Plant ResourcesMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China

Plants can produce animal cytokine-like immune peptides,among which plant elicitor peptides(Peps)derive from the C termini of their precursors(PROPEPs).Recently,the functions of Peps have been expanded beyond plant ***,a long-standing enigma is how PROPEPs are processed into ***,we report that the Ca2+-dependent type-ll metacaspases(MCs)constitute the proteolytic enzymes to mediate PROPEP processing in *** protoplasts,co-expression of PROPEP1 with type-ll MCs,including MC4 to MC9,can promote the generation of processed *** of the catalytic cysteine residue in MC4 or the conserved arginine residue preceding the Pep1 sequence blocks PROPEP1 cleavage,whereas the bacterial elicitor flg22 enhances the MC4-mediated PROPEP1 ***4 cleaves PROPEP1 in vitro and also cleaves PROPEP2 to PROPEP8,but,surprisingly,not PROPEP6 in *** swapping between PROPEP1 and PROPEP6 suggests a hidden role of the sequence context upstream of the Pep sequence for PROPEP ***22-induced PROPEP1 processing and B otrytis cinerea resistance are severely impaired in the m c4/5/6/7 quadruple-mutant *** together,our study identifies the type-ll MCs as new players in Pep signaling,and lays the foundation for understanding the regulation of multifaceted functions of Peps in plant immunity and beyond.

关键词： immunity plant elicitor peptides proteolysis metacaspases Arabidopsis

BAK1-mediated phosphorylation of canonical G protein alpha during flagellin signaling in Arabidopsis

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Journal of Integrative Plant Biology 2020年第5期62卷 690-701页

作者： Jiao Xue Ben-Qiang Gong Xinran Yao Xiangjuan Huang Jian-Feng Li Guangdong Provincial key laboratory of Plant Resources State Key Laboratory of BiocontrolMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China

Heterotrimeric G proteins consisting of Gα,Gβand Gγare conserved signaling hubs in *** analogs to canonical animal G protein-coupled receptors,plant cells are thought to use RGS1 and a yet unknown mechanism to regulate the activity of Gα.Meanwhile,the exact role of canonical Gαin plant innate immunity remains ***,we report multiple immune deficiencies in the null allele of Arabidopsis Gα(GPA1)in response to bacterial flg22 elicitor,clarifying a positive regulatory role of GPA1 in flg22 *** also detect overall increased phosphorylation of GPA1 but reduced phosphorylation at Thr^19 upon flg22 ***,flg22 could not induce phosphorylation of GPA1 T19 Aand GPA1 T19D,suggesting that the dynamic Thr^19 phosphorylation is required for GPA1 to respond to ***,flg22-induced GPA1 phosphorylation is largely abolished in the absence of BAK1 in vivo,and BAK1 could phosphorylate GPA1 but not GPA1^T19A in vitro at the phosphorylation sites identified in vivo,suggesting BAK1 is likely the kinase for GPA1 phosphorylation in response to ***,the T19A mutation could promote flg22-induced association,rather than dissociation,between GPA1 and *** together,our findings shed new insights into the function and regulation of GPA1 in Arabidopsis defense signaling.

关键词： phosphorylation Arabidopsis immunity

Multiplex and optimization of dCas9-TV-mediated gene activation in plants

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Journal of Integrative Plant Biology 2021年第4期63卷 634-645页

作者： Xiangyu Xiong Jieping Liang Zhenxiang Li Ben-Qiang Gong Jian-Feng Li Guangdong Provincial key laboratory of Plant Resources State Key Laboratory of BiocontrolMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China

Synthetic gene activators consisting of nucleasedead Cas9(dCas9)for single-guide RNA(sgRNA)-directed promoter binding and a transcriptional activation domain(TAD)represent new tools for gene activation from endogenous genomic locus in basic and applied plant ***,multiplex gene coactivation by d Cas9-TADs has not been demonstrated in whole *** is also room to optimize the performance of these ***,we report that our previously developed gene activator,dCas9-TV,could simultaneously upregulate OsGW7 and OsER1 in rice by up to 3,738 fold,with one sg RNA targeting to each *** gene coactivation could persist to at least the fourth ***,thepolycistronictRNA-sgRNAexpression under the maize ubiquitin promoter,a Pol II promoter,could cause enormous activation of these genes by up to>40,000-fold in ***,the yeast GCN4 coiled coil-mediated dCas9-TV dimerization appeared to be promising for enhancing gene ***,we successfully introduced a self-amplification loop for dCas9-TV expression in Arabidopsis to promote the transcriptional upregulation of AtFLS2,a previously characterized dCas9-TV-refractory gene with considerable basal ***,this work illustrates the robustness of dCas9-TV in multigene coactivation and provides broadly useful strategies for boosting transcriptional activation efficacy of dCas9-TADs in plants.

关键词： dCas9-TV heritability self-amplification loop multiplex gene coactivation synthetic transcription activator

Proteomics promises a new era of precision cancer medicine

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Signal Transduction and Targeted Therapy 2019年第1期4卷 562-563页

作者： Chong Wu Limin Zheng moe key laboratory of gene function and regulation State Key Laboratory of Biocontrol School of Life SciencesSun Yat-sen University510275 GuangzhouChina

A study recently published in Nature provides new insights into the proteomic heterogeneity of early-stage hepatocellular carci-noma related to hepatitis B virus infection.1 Based on quantitative proteomic and phospho-proteomic profiling,early-stage hepato-cellular carcinoma can be stratified into subtypes with different clinical outcomes,and a druggable target has been identified.

关键词： clinical stratified cancer

The working dead:repurposing inactive CRISPR-associated nucleases as programmable transcriptional regulators in plants

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aBIOTECH 2020年第1期1卷 32-40页

作者： Zhenxiang Li Xiangyu Xiong Jian-Feng Li Guangdong Provincial key laboratory of Plant Resources State Key Laboratory of BiocontrolMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China

Targeted gene manipulation is highly desirable for fundamental plant research,plant synthetic biology,and molecular *** clustered regularly interspaced short palindromic repeats-associated(Cas)nuclease is a revolutionary tool for genome editing,and has received snowballing popularity for gene knockout applications in diverse organisms including ***,the nuclease-dead Cas(dCas)proteins have been repurposed as programmable transcriptional regulators through translational fusion with portable transcriptional repression or activation domains,which has paved new ways for flexible and multiplex control over the activities of target genes of interest without the need to generate DNA ***,we review the most important breakthroughs of dCas transcriptional regulators in non-plant organisms and recent accomplishments of this growing field in *** also provide perspectives on future development directions of dCas transcriptional regulators in plant research in hope to stimulate their quick evolution and broad applications.

关键词： Nuclease-Dead Cas9(dCas9) sgRNA Transcriptional repressor Transcriptional activator Target promoter