Yong Xiong

Yale University, New Haven, Connecticut, United States

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Publications (49)546.13 Total impact

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    ABSTRACT: Background: Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy causing systolic dysfunction and heart failure. Rare variants in more than 30 genes, mostly encoding sarcomeric proteins and proteins of the cytoskeleton, have been implicated in familial DCM to date. Yet, the majority of variants causing DCM remain to be identified. The goal of the study is to identify novel mutations causing familial dilated cardiomyopathy. Results: We identify FBXO32 (ATROGIN 1), a member of the F-Box protein family, as a novel DCM-causing locus. The missense mutation affects a highly conserved amino acid and is predicted to severely impair binding to SCF proteins. This is validated by co-immunoprecipitation experiments from cells expressing the mutant protein and from human heart tissue from two of the affected patients. We also demonstrate that the hearts of the patients with the FBXO32 mutation show accumulation of selected proteins regulating autophagy. Conclusion: Our results indicate that abnormal SCF activity with subsequent impairment of the autophagic flux due to a novel FBXO32 mutation is implicated in the pathogenesis of DCM.
    Full-text · Article · Dec 2016 · Genome biology
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    ABSTRACT: HIV-1 Nef binds to the cytoplasmic region of HLA-A and HLA-B and downregulates these molecules from the surface of virus-infected cells, thus evading immune detection by CD8 + T cells. Polymorphic residues within the HLA cytoplasmic region may affect Nef’s downregulation activity. However, the effects of HLA polymorphisms on recognition by primary Nef isolates remain elusive, as do the specific Nef regions responsible for downregulation of HLA-A versus HLA-B. Here, we examined 46 Nef clones isolated from chronically HIV-1 subtype B-infected subjects for their ability to downregulate various HLA-A, HLA-B, and HLA-C molecules on the surface of virus-infected cells. Overall, HLA-B exhibited greater resistance to Nef-mediated downregulation than HLA-A, regardless of the cell type examined. As expected, no Nef clone downregulated HLA-C. Importantly, the differential abilities of patient-derived Nef clones to downregulate HLA-A and HLA-B correlated inversely with the sensitivities of HIV-infected target cells to recognition by effector cells expressing an HIV-1 Gag-specific T cell receptor. Nef codon function analysis implicated amino acid variation at position 202 (Nef-202) in differentially affecting the ability to downregulate HLA-A and HLA-B, an observation that was subsequently confirmed by experiments using Nef mutants constructed by site-directed mutagenesis. The in silico and mutagenesis analyses further suggested that Nef-202 may interact with the C-terminal Cys-Lys-Val residues of HLA-A, which are absent in HLA-B. Taken together, the results show that natural polymorphisms within Nef modulate its interaction with natural polymorphisms in the HLA cytoplasmic tails, thereby affecting the efficiency of HLA downregulation and consequent recognition by HIV-specific T cells. These results thus extend our understanding of this complex pathway of retroviral immune evasion. IMPORTANCE Recognition of genetically diverse pathogens by the adaptive immune system represents a primary strategy for host defense; however, pathogens such as HIV-1 can evade these responses to achieve persistent infection. The HIV-1 nef gene and the HLA class I locus rank among the most diverse genes of virus and host, respectively. The HIV-1 Nef protein interacts with the cytoplasmic region of HLA-A and HLA-B and downregulates these molecules to evade cellular immunity. By combining molecular, genetic, and in silico analyses, we demonstrate that patient-derived Nef clones downregulate HLA-A more effectively than HLA-B molecules. This in turn modulates the ability of HIV-specific T cells to recognize HIV-infected cells. We also identify a naturally polymorphic site at Nef codon 202 and HLA cytoplasmic motifs (GG 314,315 and CKV 339–341 ) that contribute to differential HLA downregulation by Nef. Our results highlight new interactions between HIV-1 and the human immune system that may contribute to pathogenesis.
    Preview · Article · Mar 2016 · mBio
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    ABSTRACT: Myopathies are heterogeneous disorders characterized clinically by weakness and hypotonia, usually in the absence of gross dystrophic changes. Mitochondrial dysfunction is a frequent cause of myopathy. We report a simplex case born to consanguineous parents who presented with muscle weakness, lactic acidosis, and muscle changes suggestive of mitochondrial dysfunction. Combined autozygome and exome analysis revealed a missense variant in the SLC25A42 gene, which encodes an inner mitochondrial membrane protein that imports coenzyme A into the mitochondrial matrix. Zebrafish slc25a42 knockdown morphants display severe muscle disorganization and weakness. Importantly, these features are rescued by normal human SLC25A42 RNA, but not by RNA harboring the patient's variant. Our data support a potentially causal link between SLC25A42 mutation and mitochondrial myopathy in humans.
    No preview · Article · Nov 2015 · Human Genetics
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    ABSTRACT: Purpose: Retinal dystrophies (RD) are heterogeneous hereditary disorders of the retina that are usually progressive in nature. The aim of this study was to clinically and molecularly characterize a large cohort of RD patients. Methods: We have developed a next-generation sequencing assay that allows known RD genes to be sequenced simultaneously. We also performed mapping studies and exome sequencing on familial and on syndromic RD patients who tested negative on the panel. Results: Our panel identified the likely causal mutation in >60% of the 292 RD families tested. Mapping studies on all 162 familial RD patients who tested negative on the panel identified two novel disease loci on Chr2:25,550,180-28,794,007 and Chr16:59,225,000-72,511,000. Whole-exome sequencing revealed the likely candidate as AGBL5 and CDH16, respectively. We also performed exome sequencing on negative syndromic RD cases and identified a novel homozygous truncating mutation in GNS in a family with the novel combination of mucopolysaccharidosis and RD. Moreover, we identified a homozygous truncating mutation in DNAJC17 in a family with an apparently novel syndrome of retinitis pigmentosa and hypogammaglobulinemia. Conclusion: Our study expands the clinical and allelic spectrum of known RD genes, and reveals AGBL5, CDH16, and DNAJC17 as novel disease candidates.Genet Med advance online publication 10 September 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.127.
    No preview · Article · Sep 2015 · Genetics in medicine: official journal of the American College of Medical Genetics
  • Chenxiang Tang · Xiaoyun Ji · Li Wu · Yong Xiong
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    ABSTRACT: SAMHD1 is a cellular protein that plays key roles in HIV-1 restriction and regulation of cellular dNTP levels. Mutations in SAMHD1 are also implicated in the pathogenesis of chronic lymphocytic leukemia and Aicardi-Goutieres syndrome. The anti-HIV-1 activity of SAMHD1 is negatively modulated by phosphorylation at residue T592. The mechanism underlying the effect of phosphorylation on anti-HIV-1 activity remains unclear. SAMHD1 forms tetramers that possess deoxyribonucleotide triphosphate triphosphohydrolase (dNTPase) activity, which is allosterically controlled by the combined action of GTP and all four dNTPs. Here we demonstrate that the phosphomimetic mutation T592E reduces the stability of the SAMHD1 tetramer and the dNTPase activity of the enzyme. To better understand the underlying mechanisms, we determined the crystal structures of SAMHD1 variants T592E and T592V. While the neutral substitution T592V does not perturb the structure, the charged T592E induces large conformational changes, likely triggered by electrostatic repulsion from a distinct negatively charged environment surrounding T592. The phosphomimetic mutation results in a significant decrease in the population of active SAMHD1 tetramers and hence the dNTPase activity is substantially decreased. These results provide a mechanistic understanding of how SAMHD1 phosphorylation at residue T592 may modulate its cellular and antiviral functions. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    No preview · Article · Aug 2015 · Journal of Biological Chemistry
  • Xiaofei Jia · Qi Zhao · Yong Xiong
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    ABSTRACT: Antiviral restriction factors are an integral part of the host innate immune system that protects cells from viral pathogens, such as human immunodeficiency virus (HIV). Studies of the interactions between restriction factors and HIV have greatly advanced our understanding of both the viral life cycle and basic cell biology, as well as provided new opportunities for therapeutic intervention of viral infection. Here we review the recent developments towards establishing the structural and biochemical bases of HIV inhibition by, and viral countermeasures of, the restriction factors TRIM5, MxB, APOBEC3, SAMHD1, and BST2/tetherin. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · May 2015 · Current Opinion in Structural Biology
  • Xiaoyun Ji · Yong Xiong
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    ABSTRACT: The lentivirus protein Vpx/Vpr recognizes the host restriction factor SAMHD1 at either its N- or C-terminal tail and targets it for destruction by the cellular protein degradation machinery. In this issue of Cell Host & Microbe, Schwefel et al. (2015) report the structural basis of SAMHD1 N-terminal targeting by Vpx. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Apr 2015 · Cell host & microbe
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    ABSTRACT: The von Hippel-Lindau tumor suppressor protein (VHL) recruits a Cullin 2 (Cul2) E3 ubiquitin ligase to downregulate HIF-1α, an essential transcription factor for the hypoxia response. Mutations in VHL lead to VHL disease and renal cell carcinomas. Inhibition of this pathway to upregulate erythropoietin production is a promising new therapy to treat ischemia and chronic anemia. Here, we report the crystal structure of VHL bound to a Cul2 N-terminal domain, Elongin B, and Elongin C (EloC). Cul2 interacts with both the VHL BC box and cullin box and a novel EloC site. Comparison with other cullin E3 ligase structures shows that there is a conserved, yet flexible, cullin recognition module and that cullin selectivity is influenced by distinct electrostatic interactions. Our structure provides a structural basis for the study of the pathogenesis of VHL disease and rationale for the design of novel compounds that may modulate cullin-substrate receptor interactions. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Feb 2015 · Structure
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    ABSTRACT: Neurogenetic disorders represent the largest category of Mendelian diseases in humans. They encompass a wide array of clinical presentations that range from the common e.g., intellectual disability (>1%) to the very rare, e.g., neurodegeneration with brain iron accumulation (one to three per 106) (Kalman et al., 2012 and Maulik et al., 2011). The highly prevalent involvement of the nervous system in many Mendelian disorders coincides with the observation that >80% of all human genes are expressed at some stage of brain development (Hawrylycz et al., 2012) and suggests that the brain is one of the most vulnerable organs to genetic perturbation. In fact high-resolution microarray analysis of the human genome reveals that intellectual disability is the common phenotypic denominator of genomic disorders that involve losses or gains of genes (Coe et al., 2012).
    Full-text · Article · Dec 2014 · Cell Reports
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    ABSTRACT: Human FANCD2-associated nuclease 1 (FAN1) is a DNA structure-specific nuclease involved in the processing of DNA interstrand crosslinks (ICLs). FAN1 maintains genomic stability and prevents tissue decline in multiple organs, yet it confers ICL-induced anti-cancer drug resistance in several cancer subtypes. Here we report three crystal structures of human FAN1 in complex with a 5' flap DNA substrate, showing that two FAN1 molecules form a head-to-tail dimer to locate the lesion, orient the DNA and unwind a 5' flap for subsequent incision. Biochemical experiments further validate our model for FAN1 action, as structure-informed mutations that disrupt protein dimerization, substrate orientation or flap unwinding impair the structure-specific nuclease activity. Our work elucidates essential aspects of FAN1-DNA lesion recognition and a unique mechanism of incision. These structural insights shed light on the cellular mechanisms underlying organ degeneration protection and cancer drug resistance mediated by FAN1.
    Full-text · Article · Dec 2014 · Nature Communications
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    ABSTRACT: The myxovirus resistance (Mx) proteins are interferon-induced dynamin GTPases that can inhibit a variety of viruses. Recently, MxB, but not MxA, was shown to restrict HIV-1 by an unknown mechanism that likely occurs in close proximity to the host cell nucleus and involves the viral capsid. Here, we present the crystal structure of MxB and reveal determinants involved in HIV-1 restriction. MxB adopts an extended antiparallel dimer and dimerization, but not higher-ordered oligomerization, is critical for restriction. Although MxB is structurally similar to MxA, the orientation of individual domains differs between MxA and MxB, and their antiviral functions rely on separate determinants, indicating distinct mechanisms for virus inhibition. Additionally, MxB directly binds the HIV-1 capsid, and this interaction depends on dimerization and the N terminus of MxB as well as the assembled capsid lattice. These insights establish a framework for understanding the mechanism by which MxB restricts HIV-1.
    Full-text · Article · Oct 2014 · Cell Host & Microbe
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    Xiaoyun Ji · Chenxiang Tang · Qi Zhao · Wei Wang · Yong Xiong
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    ABSTRACT: The sterile alpha motif and HD domain-containing protein 1 (SAMHD1), a dNTPase, prevents the infection of nondividing cells by retroviruses, including HIV, by depleting the cellular dNTP pool available for viral reverse transcription. SAMHD1 is a major regulator of cellular dNTP levels in mammalian cells. Mutations in SAMHD1 are associated with chronic lymphocytic leukemia (CLL) and the autoimmune condition Aicardi Goutières syndrome (AGS). The dNTPase activity of SAMHD1 can be regulated by dGTP, with which SAMHD1 assembles into catalytically active tetramers. Here we present extensive biochemical and structural data that reveal an exquisite activation mechanism of SAMHD1 via combined action of both GTP and dNTPs. We obtained 26 crystal structures of SAMHD1 in complex with different combinations of GTP and dNTP mixtures, which depict the full spectrum of GTP/dNTP binding at the eight allosteric and four catalytic sites of the SAMHD1 tetramer. Our data demonstrate how SAMHD1 is activated by binding of GTP or dGTP at allosteric site 1 and a dNTP of any type at allosteric site 2. Our enzymatic assays further reveal a robust regulatory mechanism of SAMHD1 activity, which bares resemblance to that of the ribonuclease reductase responsible for cellular dNTP production. These results establish a complete framework for a mechanistic understanding of the important functions of SAMHD1 in the regulation of cellular dNTP levels, as well as in HIV restriction and the pathogenesis of CLL and AGS.
    Full-text · Article · Sep 2014 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Fanconi anemia (FA) represents a paradigm of rare genetic diseases where the quest for cause and cure has led to seminal discoveries in cancer biology. While a total of 16 FA genes have been identified thus far, the biochemical function of many of the FA proteins remains to be elucidated. FA is rare, yet the fact that 5 FA genes are in fact familial breast cancer genes and FA gene mutations are found frequently in sporadic cancers suggest wider applicability in hematopoiesis and oncology. Establishing the interaction network involving the FA proteins and their associated partners has revealed an intersection of FA with several DNA repair pathways, including homologous recombination, DNA mismatch repair, nucleotide excision repair, and translesion DNA synthesis. Importantly, recent studies have shown a major involvement of the FA pathway in the tolerance of reactive aldehydes. Moreover, despite improved outcomes in stem cell transplantation in the treatment of FA, many challenges remain in patient care.
    Full-text · Article · Sep 2014 · Blood
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    ABSTRACT: Sir, We read with interest the article by Uhlig on the Mendelian forms of IBD.1 Mendelian forms of Crohn's disease (CD) are rare but can establish a causal link that is not usually possible by the genome-wide association study (GWAS) design. In order to accelerate the discovery of Mendelian CD, we recruited four cooperative families in which the healthy consanguineous parents had at least two affected children with early onset CD (<10 years of age), consistent with autosomal recessive inheritance (see online supplementary figure S1). With informed consent according to an Institutional Review Board approved protocol (KFSHRC RAC# 2121053), we proceeded with autozygosity mapping using AgileMultiIdeogram (http://dna.leeds.ac.uk/agile/AgileMultiIdeogram/) followed by whole-exome sequencing (WES) as previously described.2 Online supplementary table S1 shows the iterative filtering of the resulting variants based on homozygosity, predicted pathogenicity, location within the autozygome and novelty. Family 1 consists of first cousin parents, four affected and seven unaffected children. The four affected children presented with a remarkably similar clinical picture that consists of early onset IBD and severe and debilitating arthropathy. The four affected siblings shared … [Full text of this article]
    No preview · Article · Aug 2014 · Gut
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    ABSTRACT: SAMHD1, a deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase), prevents the infection of blood cells by retroviruses, including HIV, by depleting the cellular dNTP pool available for viral reverse transcription. SAMHD1 is a major regulator of cellular dNTP levels in mammalian cells. Mutations in SAMHD1 are associated with the autoimmune condition Aicardi Goutières Syndrome (AGS), whose clinical manifestations resemble congenital viral infection. The catalytic activity of SAMHD1 is regulated by allosteric binding of dGTP, which enables SAMHD1 monomers/dimers to assemble into the catalytically active tetrameric form. We have determined the crystal structure of the tetrameric human SAMHD1-dGTP complex. The structure reveals an elegant allosteric mechanism of activation via dGTP-induced assembly of the tetrameric complex from two inactive dimers. Intriguingly, GTP can also activate SAMHD1, and our data further show the binding promiscuity of other dNTPs at the allosteric site. These findings suggest a regulation system that may have a profound effect on the balancing of cellular dNTP pools. These results provide the basis for a mechanistic understanding of SAMHD1 function in HIV restriction, the pathogenesis of AGS, and regulation of cellular dNTP levels.
    Preview · Article · Aug 2014 · Acta Crystallographica Section A: Foundations and Advances
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    ABSTRACT: Focal adhesions (FAs) are macromolecular complexes that connect the actin cytoskeleton to the extracellular matrix. Dynamic turnover of FAs is critical for cell migration. Paxillin is a multi-adaptor protein that plays an important role in regulating FA dynamics. Here, we identify TRIM15, a member of the TRIpartite Motif protein family, as a paxillin-interacting factor and a component of FAs. TRIM15 localizes to focal contacts in a myosin II-independent manner by an interaction between its coiled coil domain and the LD2 motif of paxillin. Unlike other FA proteins, TRIM15 is a stable FA component with restricted mobility due to its ability to form oligomers. TRIM15-depleted cells display impaired cell migration and FA disassembly rates in addition to enlarged FAs. Thus, our studies demonstrate a cellular function for TRIM15 as a regulatory component of FA turnover and cell migration.
    Full-text · Article · Jul 2014 · Development
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    ABSTRACT: Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by severe fetal growth restriction, microcephaly, a distinct facial appearance, ichthyosis, skeletal anomalies, and perinatal lethality. The pathogenesis of NLS remains unclear despite extensive clinical and pathological phenotyping of the >70 affected individuals reported to date, emphasizing the need to identify the underlying genetic etiology, which remains unknown. In order to identify the cause of NLS, we conducted a positional-mapping study combining autozygosity mapping and whole-exome sequencing in three consanguineous families affected by NLS. Surprisingly, the NLS-associated locus identified in this study was solved at the gene level to reveal mutations in PHGDH, which is known to be mutated in individuals with microcephaly and developmental delay. PHGDH encodes the first enzyme in the phosphorylated pathway of de novo serine synthesis, and complete deficiency of its mouse ortholog recapitulates many of the key features of NLS. This study shows that NLS represents the extreme end of a known inborn error of serine metabolism and highlights the power of genomic sequencing in revealing the unsuspected allelic nature of apparently distinct clinical entities.
    Full-text · Article · May 2014 · The American Journal of Human Genetics
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    ABSTRACT: eLife digest HIV is a retrovirus that attacks the immune system, making the body increasingly susceptible to opportunistic infections and disease and eventually leading to AIDS. While antiretroviral drugs have allowed people with AIDS to live longer, there is no cure or vaccine for HIV. Two types of HIV exist, with HIV-1 being much more common and pathogenic than HIV-2. Like other ‘complex’ retroviruses, the HIV-1 genome contains genes that encode various proteins that allow the virus to disrupt the immune response of the host it is attacking. Viral protein u is a protein encoded by HIV-1 (but not HIV-2) that counteracts an antiviral protein called BST2 in the host. BST2, which is part of the host's innate immune response, prevents newly formed viruses from leaving the surface of infected cells. By counteracting BST2, viral protein u allows the virus to spread in the host more efficiently. Like many proteins, newly produced BST2 is packaged inside structures called vesicles in a part of the cell called the trans-Golgi network, and then sent to its destination. Complexes formed by various proteins make sure that the vesicles take their cargo to their correct destinations within the cell. Two adaptor protein complexes—known as AP1 and AP2—are thought to be involved the transport of BST2. However, it is not known how viral protein u stops BST2 from reaching the cell surface, or how it decreases the amount of BST2 in the cell as a whole. Jia et al. show how viral protein u and BST2 jointly interact with AP1. This interaction leads to the mistrafficking and degradation of BST2 and the counteraction of its antiviral activity. DOI: http://dx.doi.org/10.7554/eLife.02362.002
    Preview · Article · Apr 2014 · eLife Sciences
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    ABSTRACT: We have previously described a syndrome characterized by facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs (FDLAB, or Traboulsi syndrome). In view of the consanguineous nature of the affected families and the likely autosomal-recessive inheritance pattern of this syndrome, we undertook autozygosity mapping and whole-exome sequencing to identify ASPH as the disease locus, in which we identified two homozygous mutations. ASPH encodes aspartyl/asparaginyl β-hydroxylase (ASPH), which has been found to hydroxylate aspartic acid and asparagine residues on epidermal growth factor (EGF)-domain-containing proteins. The truncating and missense mutations we identified are predicted to severely impair the enzymatic function of ASPH, which suggests a possible link to other forms of ectopia lentis given that many of the genes implicated in this phenotype encode proteins that harbor EGF domains. Developmental analysis of Asph revealed an expression pattern consistent with the proposed link to the human syndrome. Indeed, Asph-knockout mice had a foreshortened snout, which corresponds to the facial abnormalities in individuals with Traboulsi syndrome. These data support a genetic basis for a syndromic form of ectopia lentis and the role of aspartyl hydroxylation in human development.
    Full-text · Article · Apr 2014 · The American Journal of Human Genetics
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    ABSTRACT: Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy with multisystem involvement. So far, 18 BBS genes have been identified and the majority of them are essential for the function of BBSome, a protein complex involved in transporting membrane proteins into and from cilia. Yet defects in the identified genes cannot account for all the BBS cases. The genetic heterogeneity of this disease pose significant challenge to the identification of additional BBS genes. In this study, we coupled human genetics with functional validation in zebrafish and identified IFT27 as a novel BBS gene (BBS19). This is the first time an IFT (intraflagellar transport) gene is implicated in the pathogenesis of BBS, highlighting the genetic complexity of this disease.
    No preview · Article · Jan 2014 · Human Molecular Genetics

Publication Stats

1k Citations
546.13 Total Impact Points

Institutions

  • 2003-2016
    • Yale University
      • Department of Molecular Biophysics and Biochemistry
      New Haven, Connecticut, United States
  • 2008
    • Johns Hopkins University
      • Department of Molecular Microbiology and Immunology
      Baltimore, Maryland, United States
  • 2007
    • Johns Hopkins Bloomberg School of Public Health
      Baltimore, Maryland, United States
  • 2005
    • Wuhan University
      • College of Life Sciences
      Wu-han-shih, Hubei, China