7 results on '"Pulan Liu"'
Search Results
2. Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents
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Yunlong Cao, Fanchong Jian, Zhiying Zhang, Ayijiang Yisimayi, Xiaohua Hao, Linlin Bao, Fei Yuan, Yuanling Yu, Shuo Du, Jing Wang, Tianhe Xiao, Weiliang Song, Ying Zhang, Pulan Liu, Ran An, Peng Wang, Yao Wang, Sijie Yang, Xiao Niu, Yuhang Zhang, Qingqing Gu, Fei Shao, Yaling Hu, Weidong Yin, Aihua Zheng, Youchun Wang, Chuan Qin, Ronghua Jin, Junyu Xiao, and Xiaoliang Sunney Xie
- Subjects
Epitopes ,Severe acute respiratory syndrome-related coronavirus ,SARS-CoV-2 ,Humans ,COVID-19 ,Combined Antibody Therapeutics ,Antibodies, Viral ,Antibodies, Neutralizing ,General Biochemistry, Genetics and Molecular Biology ,Broadly Neutralizing Antibodies - Abstract
SARS-CoV-2 Omicron sublineages have escaped most RBD-targeting therapeutic neutralizing antibodies (NAbs), which proves the previous NAb drug screening strategies deficient against the fast-evolving SARS-CoV-2. Better broad NAb drug candidate selection methods are needed. Here, we describe a rational approach for identifying RBD-targeting broad SARS-CoV-2 NAb cocktails. Based on high-throughput epitope determination, we propose that broad NAb drugs should target non-immunodominant RBD epitopes to avoid herd immunity-directed escape mutations. Also, their interacting antigen residues should focus on sarbecovirus conserved sites and associate with critical viral functions, making the antibody-escaping mutations less likely to appear. Following the criteria, a featured non-competing antibody cocktail, SA55+SA58, is identified from a large collection of broad sarbecovirus NAbs isolated from SARS convalescents. SA55+SA58 potently neutralizes ACE2-utilizing sarbecoviruses, including circulating Omicron variants, and could serve as broad SARS-CoV-2 prophylactics to offer long-term protection. Our screening strategy can also be applied to identify broad-spectrum NAb drugs against other fast-evolving viruses, such as influenza viruses.
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- 2022
3. BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection
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Yunlong Cao, Ayijiang Yisimayi, Fanchong Jian, Weiliang Song, Tianhe Xiao, Lei Wang, Shuo Du, Jing Wang, Qianqian Li, Xiaosu Chen, Yuanling Yu, Peng Wang, Zhiying Zhang, Pulan Liu, Ran An, Xiaohua Hao, Yao Wang, Rui Feng, Haiyan Sun, Lijuan Zhao, Wen Zhang, Dong Zhao, Jiang Zheng, Lingling Yu, Can Li, Na Zhang, Rui Wang, Xiao Niu, Sijie Yang, Xuetao Song, Yangyang Chai, Ye Hu, Yansong Shi, Linlin Zheng, Zhiqiang Li, Qingqing Gu, Fei Shao, Weijin Huang, Ronghua Jin, Zhongyang Shen, Youchun Wang, Xiangxi Wang, Junyu Xiao, and Xiaoliang Sunney Xie
- Subjects
Multidisciplinary ,COVID-19 Vaccines ,SARS-CoV-2 ,Immunization, Secondary ,Antibodies, Monoclonal ,COVID-19 ,Antibodies, Viral ,Antibodies, Neutralizing ,Immunity, Humoral ,Neutralization Tests ,Mutation ,Spike Glycoprotein, Coronavirus ,Immune Tolerance ,Epitopes, B-Lymphocyte ,Humans ,Angiotensin-Converting Enzyme 2 ,Antigenic Drift and Shift - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage1. The receptor binding and immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons of the spike proteins, we show that BA.2.12.1, BA.4 and BA.5 (BA.4 and BA.5 are hereafter referred collectively to as BA.4/BA.5) exhibit similar binding affinities to BA.2 for the angiotensin-converting enzyme 2 (ACE2) receptor. Of note, BA.2.12.1 and BA.4/BA.5 display increased evasion of neutralizing antibodies compared with BA.2 against plasma from triple-vaccinated individuals or from individuals who developed a BA.1 infection after vaccination. To delineate the underlying antibody-evasion mechanism, we determined the escape mutation profiles2, epitope distribution3 and Omicron-neutralization efficiency of 1,640 neutralizing antibodies directed against the receptor-binding domain of the viral spike protein, including 614 antibodies isolated from people who had recovered from BA.1 infection. BA.1 infection after vaccination predominantly recalls humoral immune memory directed against ancestral (hereafter referred to as wild-type (WT)) SARS-CoV-2 spike protein. The resulting elicited antibodies could neutralize both WT SARS-CoV-2 and BA.1 and are enriched on epitopes on spike that do not bind ACE2. However, most of these cross-reactive neutralizing antibodies are evaded by spike mutants L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1. Nevertheless, these neutralizing antibodies are largely evaded by BA.2 and BA.4/BA.5 owing to D405N and F486V mutations, and react weakly to pre-Omicron variants, exhibiting narrow neutralization breadths. The therapeutic neutralizing antibodies bebtelovimab4 and cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, whereas the S371F, D405N and R408S mutations undermine most broadly sarbecovirus-neutralizing antibodies. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.
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- 2022
4. BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron BA.1 infection
- Author
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Xiaoliang Xie, Yunlong Cao, Ayijiang Yisimayi, Fanchong Jian, Weiliang Song, Tianhe Xiao, Lei Wang, Shuo Du, jing wang, Qianqian Li, Xiaosu Chen, Peng Wang, Zhiying Zhang, Pulan Liu, Ran An, Xiaohua Hao, Yao Wang, Jing Wang, Rui Feng, Haiyan Sun, Lijuan Zhao, Wen Zhang, Dong Zhao, Jiang Zheng, Lingling Yu, Can Li, Na Zhang, Rui Wang, Xiao Niu, Sijie Yang, Xuetao Song, Linlin Zheng, Zhiqiang Li, Qingqing Gu, Fei Shao, Weijin Huang, Jin ronghua, Zhongyang Shen, Youchun Wang, Xiangxi Wang, and Junyu Xiao
- Abstract
Recent emergence of SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.2. The new variants’ receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we showed that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 shows the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization escape from the plasma of 3-dose vaccinees and, most strikingly, from vaccinated BA.1 convalescents. To delineate the underlying evasion mechanism, we determined the escaping mutation profiles, epitope distribution and Omicron sub-lineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype-induced humoral memory and elicits antibodies that neutralize both wild-type and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure of Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to wild-type SARS-CoV-2, due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths. As for therapeutic NAbs, LY-CoV1404 (Bamlanivimab) and COV2-2130 (Cilgavimab) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.
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- 2022
5. Omicron BA.2 specifically evades broad sarbecovirus neutralizing antibodies
- Author
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Yunlong Cao, Ayijiang Yisimayi, Fanchong Jian, Tianhe Xiao, Weiliang Song, Jing Wang, Shuo Du, Zhiying Zhang, Pulan Liu, Xiaohua Hao, Qianqian Li, Xiaosu Chen, Lei Wang, Peng Wang, Ran An, Yao Wang, Peng Yang, Haiyan Sun, Lijuan Zhao, Wen Zhang, Dong Zhao, Jiang Zheng, Lingling Yu, Can Li, Na Zhang, Rui Wang, Xiao Niu, Sijie Yang, Xuetao Song, Linlin Zheng, Zhiqiang Li, Qingqing Gu, Fei Shao, Weijin Huang, Youchun Wang, Zhongyang Shen, Xiangxi Wang, Ronghua Jin, Junyu Xiao, and Xiaoliang Sunney Xie
- Abstract
Omicron sub-lineage BA.2 has rapidly surged globally, accounting for over 60% of recent SARS-CoV-2 infections. Newly acquired RBD mutations and high transmission advantage over BA.1 urge the investigation of BA.2’s immune evasion capability. Here, we show that BA.2 causes strong neutralization resistance, comparable to BA.1, in vaccinated individuals’ plasma. However, BA.2 displays more severe antibody evasion in BA.1 convalescents, and most prominently, in vaccinated SARS convalescents’ plasma, suggesting a substantial antigenicity difference between BA.2 and BA.1. To specify, we determined the escaping mutation profiles1,2 of 714 SARS-CoV-2 RBD neutralizing antibodies, including 241 broad sarbecovirus neutralizing antibodies isolated from SARS convalescents, and measured their neutralization efficacy against BA.1, BA.1.1, BA.2. Importantly, BA.2 specifically induces large-scale escape of BA.1/BA.1.1-effective broad sarbecovirus neutralizing antibodies via novel mutations T376A, D405N, and R408S. These sites were highly conserved across sarbecoviruses, suggesting that Omicron BA.2 arose from immune pressure selection instead of zoonotic spillover. Moreover, BA.2 reduces the efficacy of S309 (Sotrovimab)3,4 and broad sarbecovirus neutralizing antibodies targeting the similar epitope region, including BD55-5840. Structural comparisons of BD55-5840 in complexes with BA.1 and BA.2 spike suggest that BA.2 could hinder antibody binding through S371F-induced N343-glycan displacement. Intriguingly, the absence of G446S mutation in BA.2 enabled a proportion of 440-449 linear epitope targeting antibodies to retain neutralizing efficacy, including COV2-2130 (Cilgavimab)5. Together, we showed that BA.2 exhibits distinct antigenicity compared to BA.1 and provided a comprehensive profile of SARS-CoV-2 antibody escaping mutations. Our study offers critical insights into the humoral immune evading mechanism of current and future variants.
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- 2022
6. Proteolytic processing of secretory pathway kinase Fam20C by site-1 protease promotes biomineralization
- Author
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Chih-chen Wang, Xi'e Wang, Junyu Xiao, Jianchao Zhang, Yangyang Wei, Lei Wang, Pulan Liu, and Xinxin Chen
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Pyrrolidines ,medicine.medical_treatment ,Amino Acid Motifs ,Golgi Apparatus ,symbols.namesake ,Mice ,Protein Domains ,medicine ,Animals ,Humans ,Secretion ,Kinase activity ,Protein kinase A ,Secretory pathway ,Extracellular Matrix Proteins ,Multidisciplinary ,Protease ,Osteoblasts ,Secretory Pathway ,Chemistry ,Kinase ,Casein Kinase I ,Calcium-Binding Proteins ,Serine Endopeptidases ,Cell Differentiation ,Golgi apparatus ,Biological Sciences ,Transmembrane protein ,Cell biology ,Protein Transport ,Mutation ,symbols ,Proprotein Convertases ,COP-Coated Vesicles ,HeLa Cells - Abstract
Family with sequence similarity 20C (Fam20C), the major protein kinase in the secretory pathway, generates the vast majority of the secreted phosphoproteome. However, the regulatory mechanisms of Fam20C transport, secretion, and function remain largely unexplored. Here, we show that Fam20C exists as a type II transmembrane protein within the secretory compartments, with its N-terminal signal peptide-like region serving as a membrane anchor for Golgi retention. The secretion and kinase activity of Fam20C are governed by site-1 protease (S1P), a key regulator of cholesterol homeostasis. We find that only mature Fam20C processed by S1P functions in osteoblast differentiation and mineralization. Together, our findings reveal a unique mechanism for Fam20C secretion and activation via proteolytic regulation, providing a molecular link between biomineralization and lipid metabolism.
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- 2021
7. Cryo-EM structure of human mitochondrial trifunctional protein
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Kai Liang, Jianye Dai, Ning Gao, Xiao Wang, Chu Wang, Xiaowei Chen, Pulan Liu, Junyu Xiao, and Ningning Li
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0301 basic medicine ,Mitochondrial trifunctional protein deficiency ,Mitochondrial trifunctional protein ,Protein Structure, Secondary ,03 medical and health sciences ,0302 clinical medicine ,Tetramer ,medicine ,Humans ,Protein Structure, Quaternary ,Beta oxidation ,chemistry.chemical_classification ,Liposome ,Multidisciplinary ,biology ,Mitochondrial Trifunctional Protein ,Chemistry ,Cryoelectron Microscopy ,Fatty acid ,Biological Sciences ,Lyase ,medicine.disease ,In vitro ,030104 developmental biology ,Biochemistry ,biology.protein ,030217 neurology & neurosurgery - Abstract
The mitochondrial trifunctional protein (TFP) catalyzes three reactions in the fatty acid β-oxidation process. Mutations in the two TFP subunits cause mitochondrial trifunctional protein deficiency and acute fatty liver of pregnancy that can lead to death. Here we report a 4.2-Å cryo-electron microscopy α2β2 tetrameric structure of the human TFP. The tetramer has a V-shaped architecture that displays a distinct assembly compared with the bacterial TFPs. A concave surface of the TFP tetramer interacts with the detergent molecules in the structure, suggesting that this region is involved in associating with the membrane. Deletion of a helical hairpin in TFPβ decreases its binding to the liposomes in vitro and reduces its membrane targeting in cells. Our results provide the structural basis for TFP function and have important implications for fatty acid oxidation related diseases.
- Published
- 2018
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