UCR

Plant Pathology Graduate Program



Shou-Wei Ding


Shou-Wei Ding
Office: 951-827-2341
Fax:
3202A Genomics
Office Hours: , not specified - not specified
Email: dingsw@ucr.edu

Shou-Wei Ding

Professor: Molecular Virology and Immunology

PhD -- Australian National University (Canberra, Australia)

Participating Graduate programs: (i) Cell, Molecular & Developmental Biology; (ii) Genetics, Genomics & Bioinformatics; (iii) Microbiology; (iv) Plant Pathology


Biography & Research Interests

The research programs in my lab focus on the host immune responses to RNA viruses and viral counter-defense strategies. Viruses with an RNA genome exhibit distinct genetic and immunological properties from DNA viruses. Many important human diseases (e.g. Ebola, influenza, SARS, Dengue, West Nile and polio) are caused by RNA viruses and > 70% of plant viruses are RNA viruses. RNA viruses that infect plants and animals are remarkably similar in genome structure and replication strategies. We have been taking a comparative approach to investigate the immune responses of plants, insects, nematodes and mammals to RNA viruses. Studies from my lab and others have shown that RNA viruses are targeted in plants, invertebrates and mammals by a conserved form of antiviral immunity mediated by RNA interference (RNAi). In antiviral RNAi, virus-specific dsRNA replicative intermediates are recognized and processed into small interfering RNAs (siRNAs) to guide specific virus clearance by RNAi. As a result, successful virus infection requires suppression of the antiviral immunity by a distinct class of viral proteins known as viral suppressors of RNAi (VSRs).

Awards

Fellow, American Association for the Advancement of Science, 2006

Fellow, American Academy of Microbiology, 2012

Publications

The main topics of research in my lab are:

1. Antiviral RNAi studies in plants. We began to test the hypothesis that the 2b protein of Cucumber mosaic virus (CMV) and the related tomato aspermy virus (TAV) is a viral suppressor of RNAi (VSR) after we found that 2b facilitates systemic virus spread and is responsible for the severe synergistic disease phenotype in diverse host plants (Ding et al., 1995; Ding et al., 1996). Our early publications in 1998-2004 reported the identification and characterization of the 2b protein of CMV and TAV among the first plant VSRs. Our results also revealed the VSR of TAV as an inducer of hypersensitive response (Li et al., 1999). A recent study illustrated a novel activity for the VSR of CMV to induce odor-dependent attraction to aphid vectors in the infected plants by blocking the signaling of the plant hormone jasmonic acid (Wu et al., 2016). We were among the first labs to characterize virus-derived siRNAs by deep sequencing (Aliyari et al., 2008). Bioinformatic characterization of these host-produced siRNAs to target pathogens has led to the development of novel, culture-independent approaches for rapid discovery of viruses and viroids by computational algorithms (Wu et al., 2010; Wu et al., 2012). Our recent work described the discovery of virus-activated siRNAs (vasiRNAs), a novel class of host endogenous siRNAs induced by virus infection (Cao et al., 2014). Our genetic characterization of antiviral RNAi pathways in Arabidopsis thaliana has revealed the redundant and overlapping functions of the Arabidopsis multigene families encoding Dicer-like proteins (DCLs), Argonaute proteins and RNA-dependent RNA polymerases (RDRs) in antiviral RNAi (Diaz-Pendon et al., 2007; Wang et al., 2010; Wang et al., 2011). The current focus is on the mechanistic analysis of several novel Arabidopsis antiviral RNAi pathway genes identified from a forward genetic screen using a 2b-deficient CMV mutant known to be silenced by a single genetic pathway of antiviral RNAi (Guo et al).

Guo Z, Lu JF, Wang XB, Zhan B, Li WX, Ding SW. Lipid flippases promote antiviral silencing and the biogenesis of viral and host siRNAs in Arabidopsis. Proc Natl Acad Sci USA In press.

Wu D, Qi T, Li WX, Tian H, Gao H, Wang J, Ge J, Yao R, Ren C, Wang XB, Liu YL, Kang L*, Ding SW*, Xie DX*. Viral effector protein manipulates host hormone signaling to attract insect vectors. Cell Res. In press.

Zhang T, Zhao YL, Zhao JH, Wang S, Jin Y, Chen ZQ, Fang YY, Hua CL, Ding SW, Guo HS. (2016). Cotton plants export microRNAs to inhibit virulence gene expression in a fungal pathogen. Nature Plants 2(10):16153. doi: 10.1038/nplants.2016.153.

Leibman D, Kravchik M, Wolf D, Haviv S, Weissberg M, Ophir R, Paris HS, Palukaitis P, Ding SW, Gaba V, Gal-On A. 2016. Differential expression of cucumber RNA-dependent RNA polymerase 1 genes during antiviral defense and resistance. Mol Plant Pathol. doi: 10.1111/mpp.12518. [Epub ahead of print]

Zhao JH, Fang YY, Duan CG, Fang RX, Ding SW, Guo HS. 2016. Genome-wide identification of endogenous RNA-directed DNA methylation loci associated with abundant 21-nucleotide siRNAs in Arabidopsis. Sci Rep 6:36247. doi: 10.1038/srep36247.

Wu Q, Ding SW, Zhang Y, Zhu S. 2015. Identification of viruses and viroids by next-generation sequencing and homology-dependent and homology-independent algorithms. Annu Rev Phytopathol 53:425-44.

Cao MJ, Du P, Wang XB, Yu YQ, Qiu YH, Li WX, Gal-On A, Zhou CY, Li Y, Ding SW. 2014. Virus infection triggers widespread silencing of host genes by a distinct class of endogenous siRNAs in Arabidopsis. Proc Natl Acad Sci USA111(40):14613-8

Jiang H, Lei R, Ding SW, Zhu S. 2014. Skewer: A fast and accurate adapter trimmer for Next-Generation Sequencing (NGS) paired-end reads. BMC Bioinformatics 15:182. doi:10.1186/1471-2105-15-182

Zhang Z, Qi S, Tang N, Zhang X, Chen S, Zhu P, Ma L, Cheng J, Xu Y, Lu M, Wang H, Ding SW, Li S, and Wu Q. (2014) Discovery of Replicating Circular RNAs by RNA-Seq and Computational Algorithms. PLoS Pathog 10(12): e1004553. doi:10.1371/journal.ppat.100455.

Duan CG, Fang YY, Zhou BJ, Zhao JH, Hou WN, Zhu H, Ding SW, Guo HS. 2012. Suppression of Arabidopsis ARGONAUTE1-mediated slicing, transgene-induced RNA silencing, and DNA methylation by distinct domains of the cucumber mosaic virus 2b protein. Plant Cell 24:259-274.

Wu Q, Wang Y, Cao MJ, Pantaleo V, Burgyan J, Li WX and Ding SW. 2012. Homology-independent discovery of replicating pathogenic circular RNAs by deep sequencing and a new computational algorithm. Proc Natl Acad Sci USA 109:3938-3943.

Wu Q, Luo Y, Lu R, Lau N, Lai EC, Li WX, and Ding SW. 2010. Virus discovery by deep sequencing and assembly of virus-derived small silencing RNAs. Proc Natl Acad Sci USA. 107, 1606-1611.

Wang XB, Jovel J, Udomporn P, Wang Y, Wu Q, Li WX, Gasciolli V, Vaucheret H* and Ding SW*. 2011. The 21-nucleotide, but not 22-nucleotide, viral secondary small interfering RNAs direct potent antiviral defense by two cooperative Argonautes in Arabidopsis thaliana. Plant Cell 23:1625-38.

Wang XB, Wu Q, Ito T, Cillo F, Li WX, Chen X, Yu JL, and Ding SW. 2010. RNAi-mediated viral immunity requires amplification of virus-derived siRNAs in Arabidopsis thaliana. Proc Natl Acad Sci USA 107, 484-489

Wu QF, Wang XB and Ding SW. 2010. Viral suppressors of RNA-based viral immunity: Host targets. Cell Host & Microbe 8:12-15.

Ding SW. RNA-based viral immunity. 2010. Nature Rev Immunol 10:632-44.

Aliyari R, and Ding SW. 2009. RNA-based viral immunity initiated by the Dicer family of host immune receptors. Immunol Rev 227: 176-188.

Diaz-Pendon JA and Ding SW. 2008. Direct and indirect roles of viral suppressors of RNA silencing in pathogenesis. Ann Rev Phytopath 46:303-326

Diaz-Pendon JA, Li F, Li WX, and Ding SW. 2007. Suppression of antiviral silencing by cucumber mosaic virus 2b protein in Arabidopsis is associated with drastically reduced accumulation of three classes of viral small interfering RNAs. Plant Cell19:2053-2063.

Ding SW and Voinnet O. 2007. Antiviral immunity directed by small RNAs. Cell 130:413-426

Li F, and Ding SW. 2006. Virus counterdefense: Diverse strategies for evading the RNA silencing immunity. Ann Rev Microbiol 60:503-531.

Lu R, Folimonov A, Shintaku M, Li WX, Falk BW, Dawson WO, and Ding SW. 2004. Three distinct suppressors of RNA silencing encoded by a 20-kb viral RNA genome. Proc Natl Acad Sci USA101:15742-15747.

Chen J, Li WX, Xie DX, Peng JR* & Ding SW*. 2004. Viral virulence protein suppresses RNA silencing-mediated defense but upregulates the role of miRNA in host gene expression. Plant Cell 16:1302-1313.

Ding SW, Li HW, Lu R, Li F and Li WX. 2004. RNA silencing: A conserved antiviral immunity of plants and animals. Virus Res 102, 109-115.

Ding SW. RNA silencing. 2000. Curr Opin Biotechnol 11, 152-156.Guo HS & Ding SW. 2002. A viral protein inhibits the long-range signaling activity of the gene silencing signal. EMBO J21, 398-407.

Ji LH & Ding SW. 2001. The suppressor of transgene RNA silencing encoded by cucumber mosaic virus interferes with salicylic acid-mediated virus resistance. Mol Plant-Microbe Interact14, 715-724.

Li WX and Ding SW. 2001. Viral suppressors of RNA silencing. Curr Opin Biotechnol 12, 150-154

Lucy AP, Guo HS, Li WX, & Ding SW.  2000. Suppression of post-transcriptional gene silencing by a plant viral protein localised in the nucleus. EMBO J19, 1672-1680.

Li HW, Lucy AP, Guo HS, Li WX, Ji LH, Wong SM, & Ding SW. 1999. Strong host resistance targeted against a viral suppressor of the plant gene silencing defence mechanism. EMBO J18, 2683-2691.

Brigneti G, Voinnet O, Li WX, Ji LH, Ding SW & Baulcombe DC. 1998. Viral pathogenicity determinants are suppressors of transgene silencing in Nicotiana benthamiana. EMBO J 17, 6739-6746. Retracted in 2016.

Ding SW*, Shi BJ, Li WX & Symons RH*. 1996. An interspecies hybrid RNA virus is significantly more virulent that either parental virus. Proc Natl Acad Sci USA 93, 7470-7474 (co-corresponding authors).

Ding SW*, Li WX & Symons RH*. 1995. A novel naturally occurring hybrid gene encoded by a plant RNA virus facilitates long-distance virus movement. EMBO J14, 5762-5772 (co-corresponding authors).

2. Antiviral RNAi studies in insects and nematodes. We began to investigate the antiviral function of RNAi in the animal kingdom in late 2000 because the 2b gene of CMV, shown later to encode a VSR (Li et al., 1999), shared key features with the B2 gene encoded by insect pathogen Flock house virus (FHV) despite lack of sequence similarity (Ding et al, 1995). Our first paper (Li et al., 2002) showed that B2 of FHV is a VSR in plant and Drosophila cells, FHV infection triggers production of abundant viral siRNAs, and most importantly, a B2-deficient mutant of FHV is rapidly cleared by an Argonaute2-dependent pathway of RNAi in Drosophila cells. These results provided the first evidence for an antiviral role of RNAi in the animal kingdom. My lab has subsequently identified Dicer-2, Argonaute-2 and R2D2 in the dsRNA-siRNA pathway of RNAi as the key components of antiviral RNAi in adult Drosophila; 2) revealed a highly conserved VSR mechanism that acts by binding long dsRNA to suppress its dicing into siRNAs; 3) identified the first dsRNA precursor of viral siRNAs; and 3) were the first to detect the induction of antiviral RNAi in mosquito cells and the production of virus-derived PIWI-interacting RNAs (piRNAs) in insect cells.

            My lab developed the first in vivo model in the nematode Caenorhabditis elegans for virus replication and antiviral RNAi (Lu et al., 2005). We launched replication of FHV RNA genome from an inducible transgene stably integrated in the chromosome of C. elegans. A pilot genetic screen in C. elegans identified an essential component of antiviral RNAi, Dicer-related helicase 1 (DRH-1), which is highly homologous to mammalian RIG-I-like receptors (Lu et al., 2009). Interestingly, the same antiviral RNAi pathway was shown subsequently by others to restrict the infection of a natural virus of C. elegans discovered in 2011, Orsay virus, which is most closely related to the Nodaviruses. DRH-1 acts to enhance production of viral siRNAs and both the helicase and C-terminal domains of human RIG-I can functionally replace the corresponding domains of DRH-1 to mediate antiviral RNAi in C. elegans. These studies establish a new small animal model for antiviral immunity and suggest a possible role for the classic mammalian innate immunity in antiviral RNAi.

Guo X, Zhang R, Wang J, Ding SW, Lu R. 2013. Homologous RIG-I-like helicase proteins direct RNAi-mediated antiviral immunity in C. elegans by distinct mechanisms. Proc Natl Acad Sci USA. 110:16085-90

Han YH, Luo YJ, Wu Q, Jovel J, Wang XH, Aliyari R, Han C, Li WX and Ding SW. 2011. RNA-based immunity terminates viral infection in adult Drosophila in absence of viral suppression of RNAi: Characterization of viral siRNA populations in wildtype and mutant flies. J Virol 85(24):13153-63.

Ding SW and Lu R. 2011. Virus-derived siRNAs and piRNAs in immunity and pathogenesis. Curr Opin Virol 1, 533-544

Wu Q, Luo Y, Lu R, Lau N, Lai EC, Li WX, and Ding SW. 2010. Virus discovery by deep sequencing and assembly of virus-derived small silencing RNAs. Proc Natl Acad Sci USA. 107, 1606-1611.

Lu R, Yigit E, Li WX and Ding SW. 2009. An RIG-I-like RNA helicase mediates antiviral RNAi downstream of viral siRNA biogenesis in Caenorhabditis elegans. PLoS Pathogens 5(2): e1000286

Aliyari R, Wu QF, L HW, Wang XH, Li F, Green LD Han CS, Li WX, and Ding SW. 2008. Mechanism of induction and suppression of antiviral immunity directed by virus-derived small RNAs in DrosophilaCell Host & Microbe 4:387-397.

Wang XH, Aliyari R, Li WX, Li HW, Kim K, Carthew R, Atkinson P, and Ding SW. 2006. RNA interference directs innate immunity against viruses in adult Drosophila. Science 312:452-454.

Lu R, Maduro M, Li F, Li HW, Maduro G, Li WX and Ding SW. 2005. Animal virus replication and RNAi-mediated antiviralin Caenorhabditis elegans. Nature 436:1040-1043.

Li HW, and Ding SW. 2005. Antiviral silencing in animals. FEBS Lett 579, 5965-5973

Li WX, Li HW, Lu R, Li F, Dus M, Atkinson P, Johnson KL, Garcia-Sastre A, Brydon E, Ball LA, Palese P & Ding SW. (2004) Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing. Proc Natl Acad Sci USA101:1350-1355.

Li HW, Li WX, & Ding SW. 2002. Induction and suppression of RNA silencing by an animal virus. Science 296, 1319-1321

3. Antiviral RNAi in mammals. We have recently provided several lines of evidence for an antiviral function of RNAi in mammals. Our first set of studies utilized Nodamura virus (NoV), which is mosquito transmissible, lethally infects suckling mice and hamsters, and is in the same virus genus as FHV. We showed that infection of suckling mice by mutants of NoV expressing either no B2 protein (NoVDB2) or a B2 mutant (B2-R59Q) unable to suppress Dicer processing of long dsRNA triggers production of highly abundant virus-derived siRNAs predominantly 22 nucleotides in length. Similar to plant and insect virus mutants defective in the expression of the cognate VSR, both NoVDB2 and NoVB2-R59Q become non-virulent and are rapidly cleared in suckling mice (Li et al., 2013). NoVDB2 infection is also defective in mouse embryonic stem cells (mESCs), capable of Dicer-mediated biogenesis and Argonaute loading of abundant viral siRNAs in response to the infection with Encephalomyocarditis virus or NoVDB2 (Maillard et al., 2013). However, NoVDB2 replicates to significantly higher levels in mESCs after all of the four Argonaute genes are genetically knocked out (Maillard et al., 2013).

We reported previously that the non-structural protein 1 (NS1) of influenza A virus (IAV) can suppress antiviral RNAi in Drosophila cells (Li et al., 2004). Recently, we show that distinct mature human somatic cells produce highly abundant viral siRNAs in response to the infection with IAV mutants deficient in the expression of NS1 (Li et al., 2016). These influenza viral siRNAs are produced by the wild type human Dicer enzyme and their production is strongly suppressed both by NS1 and by VP35 of Ebola and Marburg viruses. Notably, IAV and two additional RNA viruses replicated to higher levels in primary mouse embryonic fibroblasts made defective in RNAi by introducing a specific mutation to abolish the slicing activity of Argonaute-2 (Li et al., 2016). 


Li Y, Basavappa M, Lu JF, Dong S, Cronkite DA, Prior JT, Reinecker HC, Hertzog P, Han Y, Li WX, Cheloufi S, Karginov FV, Ding SW*, Jeffrey KL* 2016. Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells. Nature Microbiol 2:16250. doi: 10.1038/nmicrobiol.2016.250

Fan X, Dong S, Li Y, Ding SW, Wang M. 2015. RIG-I-dependent antiviral immunity is effective against an RNA virus encoding a potent suppressor of RNAi. Biochem Biophys Res Commun 460(4):1035-40.

Li Y, Lu JF, Han YH, Fan XX and Ding SW. 2013. RNA interference functions as an antiviral immunity mechanism in mammals. Science 342:231-234.

Maillard PV, Ciaudo C, Marchais A, Li Y, Jay F, Ding SW, Voinnet O. Antiviral RNA interference in mammalian cells. Science 342:235-238.

Gaulke C, Porter M, Han YH, Sankaran-Walters S, Grishina I, George M, Dang A, Ding SW, Jiang G, Korf I, Dandekar S 2014. Intestinal epithelial barrier disruption through altered mucosal microRNA expression in human immunodeficiency virus and simian immunodeficiency virus infections. J Virol 88:6268–6280

Li WX, Li HW, Lu R, Li F, Dus M, Atkinson P, Johnson KL, Garcia-Sastre A, Brydon E, Ball LA, Palese P & Ding SW. (2004) Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing. Proc Natl Acad Sci USA101:1350-1355.


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