Jiqiang (Lanny) Ling, Ph.D.

Assistant Professor

Contact Email: jling12@umd.edu

Office Phone: 301.405.1035

Lab Phone: 

Lab: 2202 Microbiology Building

Office Address: 2202C Microbiology Building

URL

Graduate Program Affiliations

 

 

Research Interests

 

Protein synthesis is a central process in all cells, and the protein synthesis machinery has been a major target for antibiotics. The rise of multi-drug resistant bacteria and a shortage of new antibiotics demand further studies of the protein synthesis machinery and the mechanisms of antibiotic resistance. Defects during protein synthesis in humans also lead to cardiovascular and neurological diseases, yet the disease-causing mechanisms remain largely unclear. The overall goal of our laboratory is to understand the molecular basis of protein synthesis and its disease connection.  We are combining biochemical, single-cell, genetic, genomic, and proteomic approaches to study the following research areas:

1. Physiological impact of protein mistranslation

Protein mistranslation (reduced translation fidelity) has been shown to cause growth defects in bacteria, mitochondrial dysfunction in yeast, and neurodegeneration in mammals. It is therefore commonly thought that mistranslation is harmful to cells and needs to be avoided. Surprisingly, we and others have shown that mistranslation is increased during stress conditions, leading to the hypothesis that mistranslation plays adaptive roles under certain stress conditions. We are currently investigating the fitness changes caused by mistranslation and the underlying molecular mechanisms.

Most related publications

·       Ling J, So BR, Yadavalli SS, Roy H, Shoji S, Fredrick K, Musier-Forsyth K, Ibba M (2009) Resampling and editing of mischarged tRNA prior to translation elongation. Mol. Cell 33:654-660. Featured article. PMID: 19285947

·       Ling J, Söll D (2010) Oxidative stress induces protein mistranslation through inactivation of an aminoacyl-tRNA synthetase editing site. Proc. Natl. Acad. Sci. USA 107:4028-4033. PMID: 20160114

·       Ling J, Cho C, Guo L, Aerni H, Rinehart J, Söll D (2012) Protein aggregation caused by aminoglycoside action is prevented by a hydrogen peroxide scavenger. Mol. Cell 48:713-722. Previewed by Drummond in Mol. Cell. PMID: 23122414

·       Wu J, Fang Y, Ling J. (2014) Mechanism of oxidant-induced mistranslation by threonyl-tRNA synthetase. Nucleic Acids Res. (Corresponding author). 42:6523-6531. PMID: 24744241

·       Fan Y, Wu J, Ung MH, DeLay N, Cheng C, Ling J. (2015) Protein mistranslation protects bacteria against oxidative stress. Nucleic Acids Res. (Corresponding author). 43:1740-1748. PMID: 25578967

 

2. Translation fidelity in single cells

Previous studies of translation fidelity have mostly focused on the population level, and little is known about the distribution and regulation of translation fidelity among genetically-identical single cells. It has been shown that gene expression is stochastic and noisy, which can lead to phenotypic heterogeneity among individual cells that may benefit the population during environmental changes and stress conditions. Our current understanding of gene expression noise is mostly limited to the transcription level. We have recently developed a dual-fluorescence reporter system to visualize translation errors in single bacterial cells, and applied these reporters to determine heterogeneity of stop codon readthrough. We are currently interested in understanding the level and sources of translation noise and how such heterogeneity in single cells affects population fitness.

UGA Readthrough Is Heterogeneous among Single Cells. YFP and mCherry fluorescence in single bacterial cells carrying either the m-y or m-TGA-y reporter. The YFP/mCherry ratio of the m-TGA-y reporter indicates the UGA readthrough level, which varies from cell to cell within a genetically-identical population.

Most related publications

·       Ling J*, O’Donoghue*, Söll D (2015) Genetic code flexibility in microorganisms: novel mechanisms and impact on microbial physiology. Nat. Rev. Microbiol. 13:707-721. (*Equal contributions). PMID: 26411296

·       Fan Y, Evans CR, Barber KW, Banerjee K, Weiss KJ, Margolin W, Igoshin OA, Rinehart J, Ling J. (2017) Heterogeneity of stop codon readthrough in single bacterial cells and implications for population fitness. Mol Cell. 67:1-11. (Corresponding author) Featured article. PMID: 28781237

 

3. Protein synthesis defects and human diseases

Recent advances in genome sequencing and genetics have allowed a rapid growth of identified mutations in aaRSs that cause human diseases. In collaboration with Dr. Christopher Walsh and Ganesh Mochida’s laboratories, we have identified novel disease-causing mutations in QARS (encoding glutaminyl-tRNA synthetase) and AARS (alanyl-tRNA synthetase). Patients carrying such mutations develop microcephaly and seizure during early childhood. We are currently exploring the molecular mechanism by which QARS and AARS defects impair cellular function.

Most related publications

·       Zhang X*, Ling J*, Barcia G*, Jing L, Wu J, Barry BJ, Mochida GH, Hill RS, Weimer JM, Stein Q, Poduri A, Partlow JN, Ville D, Dulac O, Yu TW, Lam AT, Servattalab S, Rodriguez J, Boddaert N, Munnich A, Colleaux L, Zon LI, Söll D, Walsh CA, Nabbout R. (2014) Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. Am. J. Hum. Genet. (*Equal contributions). 94:547-558. PMID: 24656866

·       Ognjenović J, Wu J, Matthies D, Baxa U, Subra maniam S, Ling J, Simonović M. (2016) The crystal structure of human GlnRS provides basis for the development of neurological disorders. Nucleic Acids Res. (Corresponding author). 44:3420-3431. PMID: 26869582

·       TarailoGraovac M, Shyr C, Ross CJ, Horvath GA, Salvarinova R, Ye XC, Zhang LH, Bhavsar AP, Lee JJY, Drögemöller BI, Abdelsayed M, Alfadhel M, Armstrong L, Baumgartner MR, Burda P, Connolly MB, Cameron J, Demos M, Dewan T, Dionne J, Evans AM, Friedman JM, Garber I, Lewis S, Ling J, Mandal R, Mattman A, McKinnon M, Michoulas A, Metzger D, Ogunbayo OA, Rakic B, Rozmus J, Ruben P, Sayson B, Santra S, Schultz KR, Selby K, Shekel P, Sirrs S, Skrypnyk C, SupertiFurga A, Turvey SE, Van Allen MI, Wishart D, Wu J, Wu J, Zafeiriou D, Kluijtmans L, Wevers RA, Eydoux P, Lehman AM, Vallance H, StocklerIpsiroglu S, Sinclair G, Wasserman WW, and Van Karnebeek CD (2016) Exome sequencing and the management of neurometabolic disorders. N. Engl. J. Med. 374:2246-2255. PMID: 27276562

·       Nakayama T, Wu J, Galvin-Parton P, Weiss J, Andriola MR, Hill RS, Vaughan D, El-Quessny M, Barry BJ, Partlow JN, Barkovich AJ, Ling J, Mochida GH (2017) Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy. Hum. Mutat. Epub ahead of print. (Corresponding author) PMID: 28493438

·       Leshinsky-Silver E, Ling J, Wu J, Vinkler C, Yosovich K, Bahar S, Yanoov-Sharav M, Lerman-Sagie T, Lev D. (2017) Severe growth deficiency, microcephaly, intellectual disability, and characteristic facial features are due to a homozygous QARS mutation. Neurogenetics. 18:141-146. PMID: 28620870

 

Selected Publications

·       Fan Y, Evans CR, Barber KW, Banerjee K, Weiss KJ, Margolin W, Igoshin OA, Rinehart J, Ling J. (2017) Heterogeneity of stop codon readthrough in single bacterial cells and implications for population fitness. Mol Cell. 67:1-11. (Corresponding author) Featured article. PMID: 28781237

·       Fan Y, Wu J, Ung MH, DeLay N, Cheng C, Ling J. (2015) Protein mistranslation protects bacteria against oxidative stress. Nucleic Acids Res. (Corresponding author). 43:1740-1748. PMID: 25578967

·       Wu J, Fang Y, Ling J. (2014) Mechanism of oxidant-induced mistranslation by threonyl-tRNA synthetase. Nucleic Acids Res. (Corresponding author). 42:6523-6531. PMID: 24744241

·       Ling J, Cho C, Guo L, Aerni H, Rinehart J, Söll D (2012) Protein aggregation caused by aminoglycoside action is prevented by a hydrogen peroxide scavenger. Mol. Cell 48:713-722. Previewed by Drummond in Mol. Cell. PMID: 23122414

·       Ling J, Söll D (2010) Oxidative stress induces protein mistranslation through inactivation of an aminoacyl-tRNA synthetase editing site. Proc. Natl. Acad. Sci. USA 107:4028-4033. PMID: 20160114

·       Ling J, So BR, Yadavalli SS, Roy H, Shoji S, Fredrick K, Musier-Forsyth K, Ibba M (2009) Resampling and editing of mischarged tRNA prior to translation elongation. Mol. Cell 33:654-660. Featured article. PMID: 19285947

 

Complete List of Published Work

http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/47346803/?sort=date&direction=descending

 

Positions

Students and postdoctoral candidates who are interested in joining Dr. Ling’s lab should email: jling12@umd.edu

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