Honors & Awards

  • Award for Outstanding Self-Financed Students Abroad, Ministry of Education of China (2019)
  • MCHRI postdoctoral support, Stanford MCHRI (2022-2024)

Professional Education

  • Doctor of Philosophy, California Institute of Technology (2020)
  • Bachelor of Science, Wuhan University (2011)

Stanford Advisors

All Publications

  • Alternative splicing of latrophilin-3 controls synapse formation. Nature Wang, S., DeLeon, C., Sun, W., Quake, S. R., Roth, B. L., Südhof, T. C. 2024


    The assembly and specification of synapses in the brain is incompletely understood1-3. Latrophilin-3 (encoded by Adgrl3, also known as Lphn3)-a postsynaptic adhesion G-protein-coupled receptor-mediates synapse formation in the hippocampus4 but the mechanisms involved remain unclear. Here we show in mice that LPHN3 organizes synapses through a convergent dual-pathway mechanism: activation of Gαs signalling and recruitment of phase-separated postsynaptic protein scaffolds. We found that cell-type-specific alternative splicing of Lphn3 controls the LPHN3 G-protein-coupling mode, resulting in LPHN3 variants that predominantly signal through Gαs or Gα12/13. CRISPR-mediated manipulation of Lphn3 alternative splicing that shifts LPHN3 from a Gαs- to a Gα12/13-coupled mode impaired synaptic connectivity as severely as the overall deletion of Lphn3, suggesting that Gαs signalling by LPHN3 splice variants mediates synapse formation. Notably, Gαs-coupled, but not Gα12/13-coupled, splice variants of LPHN3 also recruit phase-transitioned postsynaptic protein scaffold condensates, such that these condensates are clustered by binding of presynaptic teneurin and FLRT ligands to LPHN3. Moreover, neuronal activity promotes alternative splicing of the synaptogenic Gαs-coupled variant of LPHN3. Together, these data suggest that activity-dependent alternative splicing of a key synaptic adhesion molecule controls synapse formation by parallel activation of two convergent pathways: Gαs signalling and clustered phase separation of postsynaptic protein scaffolds.

    View details for DOI 10.1038/s41586-023-06913-9

    View details for PubMedID 38233523

    View details for PubMedCentralID 8186004

  • Ribosome profiling reveals multiple roles of SecA in cotranslational protein export. Nature communications Zhu, Z., Wang, S., Shan, S. O. 2022; 13 (1): 3393


    SecA, an ATPase known to posttranslationally translocate secretory proteins across the bacterial plasma membrane, also binds ribosomes, but the role of SecA's ribosome interaction has been unclear. Here, we used a combination of ribosome profiling methods to investigate the cotranslational actions of SecA. Our data reveal the widespread accumulation of large periplasmic loops of inner membrane proteins in the cytoplasm during their cotranslational translocation, which are specifically recognized and resolved by SecA in coordination with the proton motive force (PMF). Furthermore, SecA associates with 25% of secretory proteins with highly hydrophobic signal sequences at an early stage of translation and mediates their cotranslational transport. In contrast, the chaperone trigger factor (TF) delays SecA engagement on secretory proteins with weakly hydrophobic signal sequences, thus enforcing a posttranslational mode of their translocation. Our results elucidate the principles of SecA-driven cotranslational protein translocation and reveal a hierarchical network of protein export pathways in bacteria.

    View details for DOI 10.1038/s41467-022-31061-5

    View details for PubMedID 35697696

  • The molecular mechanism of cotranslational membrane protein recognition and targeting by SecA NATURE STRUCTURAL & MOLECULAR BIOLOGY Wang, S., Jomaa, A., Jaskolowski, M., Yang, C., Ban, N., Shan, S. 2019; 26 (10): 919-+


    Cotranslational protein targeting is a conserved process for membrane protein biogenesis. In Escherichia coli, the essential ATPase SecA was found to cotranslationally target a subset of nascent membrane proteins to the SecYEG translocase at the plasma membrane. The molecular mechanism of this pathway remains unclear. Here we use biochemical and cryoelectron microscopy analyses to show that the amino-terminal amphipathic helix of SecA and the ribosomal protein uL23 form a composite binding site for the transmembrane domain (TMD) on the nascent protein. This binding mode further enables recognition of charged residues flanking the nascent TMD and thus explains the specificity of SecA recognition. Finally, we show that membrane-embedded SecYEG promotes handover of the translating ribosome from SecA to the translocase via a concerted mechanism. Our work provides a molecular description of the SecA-mediated cotranslational targeting pathway and demonstrates an unprecedented role of the ribosome in shielding nascent TMDs.

    View details for DOI 10.1038/s41594-019-0297-8

    View details for Web of Science ID 000488970400015

    View details for PubMedID 31570874

    View details for PubMedCentralID PMC6858539

  • SecA mediates cotranslational targeting and translocation of an inner membrane protein JOURNAL OF CELL BIOLOGY Wang, S., Yang, C., Shan, S. 2017; 216 (11): 3639–53


    Protein targeting to the bacterial plasma membrane was generally thought to occur via two major pathways: cotranslational targeting by signal recognition particle (SRP) and posttranslational targeting by SecA and SecB. Recently, SecA was found to also bind ribosomes near the nascent polypeptide exit tunnel, but the function of this SecA-ribosome contact remains unclear. In this study, we show that SecA cotranslationally recognizes the nascent chain of an inner membrane protein, RodZ, with high affinity and specificity. In vitro reconstitution and in vivo targeting assays show that SecA is necessary and sufficient to direct the targeting and translocation of RodZ to the bacterial plasma membrane in an obligatorily cotranslational mechanism. Sequence elements upstream and downstream of the RodZ transmembrane domain dictate nascent polypeptide selection by SecA instead of the SRP machinery. These findings identify a new route for the targeting of inner membrane proteins in bacteria and highlight the diversity of targeting pathways that enables an organism to accommodate diverse nascent proteins.

    View details for DOI 10.1083/jcb.201704036

    View details for Web of Science ID 000414609700020

    View details for PubMedID 28928132

    View details for PubMedCentralID PMC5674894

  • CapZ regulates autophagosomal membrane shaping by promoting actin assembly inside the isolation membrane NATURE CELL BIOLOGY Mi, N., Chen, Y., Wang, S., Chen, M., Zhao, M., Yang, G., Ma, M., Su, Q., Luo, S., Shi, J., Xu, J., Guo, Q., Gao, N., Sun, Y., Chen, Z., Yu, L. 2015; 17 (9): 1112-+


    A fundamental question regarding autophagosome formation is how the shape of the double-membrane autophagosomal vesicle is generated. Here we show that in mammalian cells assembly of an actin scaffold inside the isolation membrane (the autophagosomal precursor) is essential for autophagosomal membrane shaping. Actin filaments are depolymerized shortly after starvation and actin is assembled into a network within the isolation membrane. When formation of actin puncta is disrupted by an actin polymerization inhibitor or by knocking down the actin-capping protein CapZβ, isolation membranes and omegasomes collapse into mixed-membrane bundles. Formation of actin puncta is PtdIns(3)P dependent, and inhibition of PtdIns(3)P formation by treating cells with the PI(3)K inhibitor 3-MA, or by knocking down Beclin-1, abolishes the formation of actin puncta. Binding of CapZ to PtdIns(3)P, which is enriched in omegasomes, stimulates actin polymerization. Our findings illuminate the mechanism underlying autophagosomal membrane shaping and provide key insights into how autophagosomes are formed.

    View details for DOI 10.1038/ncb3215

    View details for Web of Science ID 000361113700005

    View details for PubMedID 26237647

  • Regulation by a chaperone improves substrate selectivity during cotranslational protein targeting PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ariosa, A., Lee, J., Wang, S., Saraogi, I., Shan, S. 2015; 112 (25): E3169–E3178


    The ribosome exit site is a crowded environment where numerous factors contact nascent polypeptides to influence their folding, localization, and quality control. Timely and accurate selection of nascent polypeptides into the correct pathway is essential for proper protein biogenesis. To understand how this is accomplished, we probe the mechanism by which nascent polypeptides are accurately sorted between the major cotranslational chaperone trigger factor (TF) and the essential cotranslational targeting machinery, signal recognition particle (SRP). We show that TF regulates SRP function at three distinct stages, including binding of the translating ribosome, membrane targeting via recruitment of the SRP receptor, and rejection of ribosome-bound nascent polypeptides beyond a critical length. Together, these mechanisms enhance the specificity of substrate selection into both pathways. Our results reveal a multilayered mechanism of molecular interplay at the ribosome exit site, and provide a conceptual framework to understand how proteins are selected among distinct biogenesis machineries in this crowded environment.

    View details for DOI 10.1073/pnas.1422594112

    View details for Web of Science ID 000356731300008

    View details for PubMedID 26056263

    View details for PubMedCentralID PMC4485088

  • Isolation and Molecular Identification of Auxotrophic Mutants to Develop a Genetic Manipulation System for the Haloarchaeon Natrinema sp J7-2 ARCHAEA-AN INTERNATIONAL MICROBIOLOGICAL JOURNAL Lv, J., Wang, S., Wang, Y., Huang, Y., Chen, X. 2015; 2015: 483194


    Our understanding of the genus Natrinema is presently limited due to the lack of available genetic tools. Auxotrophic markers have been widely used to construct genetic systems in bacteria and eukaryotes and in some archaeal species. Here, we isolated four auxotrophic mutants of Natrinema sp. J7-2, via 1-methyl-3-nitro-1-nitroso-guanidin mutagenesis, and designated them as J7-2-1, J7-2-22, J7-2-26, and J7-2-52, respectively. The mutant phenotypes were determined to be auxotrophic for leucine (J7-2-1), arginine (J7-2-22 and J7-2-52), and lysine (J7-2-26). The complete genome and the biosynthetic pathways of amino acids in J7-2 identified that the auxotrophic phenotype of three mutants was due to gene mutations in leuB (J7-2-1), dapD (J7-2-26), and argC (J7-2-52). These auxotrophic phenotypes were employed as selectable makers to establish a transformation method. The transformation efficiencies were determined to be approximately 10(3) transformants per µg DNA. And strains J7-2-1 and J7-2-26 were transformed into prototrophic strains with the wild type genomic DNA, amplified fragments of the corresponding genes, or the integrative plasmids carrying the corresponding genes. Additionally, exogenous genes, bgaH or amyH gene, were expressed successfully in J7-2-1. Thus, we have developed a genetic manipulation system for the Natrinema genus based on the isolated auxotrophic mutants of Natrinema sp. J7-2.

    View details for DOI 10.1155/2015/483194

    View details for Web of Science ID 000355550700001

    View details for PubMedID 26089742

    View details for PubMedCentralID PMC4454726

  • Construction of a shuttle expression vector with a promoter functioning in both halophilic Archaea and Bacteria FEMS MICROBIOLOGY LETTERS Lv, J., Wang, S., Zeng, C., Huang, Y., Chen, X. 2013; 349 (1): 9–15


    A shuttle expression vector, designated as pAJ, was constructed based on the Haloferax volcanii-Escherichia coli shuttle vector pSY1. This new construct contains the amyH promoter from Haloarcula hispanica and was able to confer the promoter activity in both Hfx. volcanii and E. coli. pAJ successfully expressed proteins in Hfx. volcanii or E. coli, rendering it feasible to express target proteins in corresponding domains. In addition, pAJ contains a multiple cloning site with 11 restriction sites and a 6×His tag sequence, and the vector size was decreased to 8903 bp. To the best of our knowledge, pAJ is the first reported shuttle expression vector that can express proteins in both Bacteria and Archaea. Importantly, pAJ can even express the haloarchaeal heat shock protein DnaK in both domains. In conclusion, this novel vector only provides researchers with a new means to manipulate genes or express proteins in Haloarchaea but also serves as a convenient tool for the comparative study of the function of some highly conserved genes in Haloarchaea and in Bacteria.

    View details for DOI 10.1111/1574-6968.12278

    View details for Web of Science ID 000326659000002

    View details for PubMedID 24106795

  • Temperate membrane-containing halophilic archaeal virus SNJ1 has a circular dsDNA genome identical to that of plasmid pHH205 VIROLOGY Zhang, Z., Liu, Y., Wang, S., Yang, D., Cheng, Y., Hu, J., Chen, J., Mei, Y., Shen, P., Bamford, D. H., Chen, X. 2012; 434 (2): 233–41


    A temperate haloarchaeal virus, SNJ1, was induced from the lysogenic host, Natrinema sp. J7-1, with mitomycin C, and the virus produced plaques on lawns of Natrinema sp. J7-2. Optimization of the induction conditions allowed us to increase the titer from ~10(4) PFU/ml to ~10(11) PFU/ml. Single-step growth curves exhibited a burst size of ~100 PFU/cell. The genome of SNJ1 was observed to be a circular, double-stranded DNA (dsDNA) molecule (16,341 bp). Surprisingly, the sequence of SNJ1 was identical to that of a previously described plasmid, pHH205, indicating that this plasmid is the provirus of SNJ1. Several structural protein-encoding genes were identified in the viral genome. In addition, the comparison of putative packaging ATPase sequences from bacterial, archaeal and eukaryotic viruses, as well as the presence of lipid constituents from the host phospholipid pool, strongly suggest that SNJ1 belongs to the PRD1-type lineage of dsDNA viruses, which have an internal membrane.

    View details for DOI 10.1016/j.virol.2012.05.036

    View details for Web of Science ID 000312509300012

    View details for PubMedID 22784791