William G. Walton

University of North Carolina at Chapel Hill

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Matthew R. Redinbo

University of North Carolina at Chapel Hill

Samuel J. Pellock

University of Washington

Jeffery L. Dangl

University of North Carolina at Chapel Hill

Sridhar Mani

Albert Einstein College of Medicine

Adam D. Lietzan

University of North Carolina at Chapel Hill

Robert Tarran

University of Kansas Medical Center

Michael S. Little

Montclair State University

Benjamin C. Creekmore

University of North Carolina at Chapel Hill

Kristen A. Biernat

Warsaw University of Technology

Arne Schön

Johns Hopkins University

Cooperative Institutions

University of North Carolina at Chapel Hill

133

University of North Carolina Health Care

UNC Lineberger Comprehensive Cancer Center

Albert Einstein College of Medicine

Lung Institute

Imperial College London

University of Perugia

Howard Hughes Medical Institute

Indiana University School of Medicine

Palacký University Olomouc

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

An Atlas of β-Glucuronidases in the Human Intestinal Microbiome

Structure (2017)

Rebecca M. Pollet Emma H. D’Agostino William G. Walton Yongmei Xu Michael S. Little

Intestinal Microbiome

10.1016/j.str.2017.05.003

Cite

Citations (211)

An unusual CsrA family member operates in series with RsmA to amplify posttranscriptional responses inPseudomonas aeruginosa

Proceedings of the National Academy of Sciences (2013)

Jeremiah N. Marden Manisha R. Diaz William G. Walton Cindy J. Gode Laurie Betts

Members of the CsrA family of prokaryotic mRNA-binding proteins alter the translation and/or stability of transcripts needed for numerous global physiological processes. The previously described CsrA family member in Pseudomonas aeruginosa (RsmA) plays a central role in determining infection modality by reciprocally regulating processes associated with acute (type III secretion and motility) and chronic (type VI secretion and biofilm formation) infection. Here we describe a second, structurally distinct RsmA homolog in P. aeruginosa (RsmF) that has an overlapping yet unique regulatory role. RsmF deviates from the canonical 5 β-strand and carboxyl-terminal α-helix topology of all other CsrA proteins by having the α-helix internally positioned. Despite striking changes in topology, RsmF adopts a tertiary structure similar to other CsrA family members and binds a subset of RsmA mRNA targets, suggesting that RsmF activity is mediated through a conserved mechanism of RNA recognition. Whereas deletion of rsmF alone had little effect on RsmA-regulated processes, strains lacking both rsmA and rsmF exhibited enhanced RsmA phenotypes for markers of both type III and type VI secretion systems. In addition, simultaneous deletion of rsmA and rsmF resulted in superior biofilm formation relative to the wild-type or rsmA strains. We show that RsmF translation is derepressed in an rsmA mutant and demonstrate that RsmA specifically binds to rsmF mRNA in vitro, creating a global hierarchical regulatory cascade that operates at the posttranscriptional level.

Protein family

Wild type

10.1073/pnas.1307217110

Cite

Citations (89)

Identification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor

Nature Communications (2017)

Tongde Wu Julianne Huang Patrick J. Moore Michael S. Little William G. Walton

Abstract Asthma is a chronic airway disease characterized by inflammation, mucus hypersecretion and abnormal airway smooth muscle (ASM) contraction. Bacterial permeability family member A1, BPIFA1, is a secreted innate defence protein. Here we show that BPIFA1 levels are reduced in sputum samples from asthmatic patients and that BPIFA1 is secreted basolaterally from healthy, but not asthmatic human bronchial epithelial cultures (HBECs), where it suppresses ASM contractility by binding to and inhibiting the Ca 2+ influx channel Orai1. We have localized this effect to a specific, C-terminal α-helical region of BPIFA1. Furthermore, tracheas from Bpifa1 − / − mice are hypercontractile, and this phenotype is reversed by the addition of recombinant BPIFA1. Our data suggest that BPIFA1 deficiency in asthmatic airways promotes Orai1 hyperactivity, increased ASM contraction and airway hyperresponsiveness. Strategies that target Orai1 or the BPIFA1 deficiency in asthma may lead to novel therapies to treat this disease.

Orai1

Contractility

10.1038/ncomms14118

Cite

Citations (49)

Crystal structure of the MarR family transcriptional regulator from Variovorax paradoxus bound to 2,4-Dichlorophenoxyacetic acid

William G. Walton Matthew R. Redinbo Jeffery L. Dangl

10.2210/pdb7kki/pdb

Cite

Citations (0)

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Proceedings of the National Academy of Sciences (2020)

Aadra P. Bhatt Samuel J. Pellock Kristen A. Biernat William G. Walton Bret D. Wallace

Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models. We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immune-deficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan's effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage.

Anticancer drug

10.1073/pnas.1918095117

Cite

Citations (155)

Targeting Regorafenib-Induced Toxicity through Inhibition of Gut Microbial β-Glucuronidases

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2019)

Samantha M. Ervin Ronan P. Hanley Lauren Lim William G. Walton Kenneth H. Pearce

Regorafenib

10.17615/3qds-f928

Cite

Citations (0)

Identification of the SPLUNC1 ENaC-inhibitory domain yields novel strategies to treat sodium hyperabsorption in cystic fibrosis airway epithelial cultures

AJP Lung Cellular and Molecular Physiology (2013)

Carey Hobbs Maxime G. Blanchard Omar Alijevic Chong Da Tan Stephan Kellenberger

The epithelial sodium channel (ENaC) is responsible for Na + and fluid absorption across colon, kidney, and airway epithelia. Short palate lung and nasal epithelial clone 1 (SPLUNC1) is a secreted, innate defense protein and an autocrine inhibitor of ENaC that is highly expressed in airway epithelia. While SPLUNC1 has a bactericidal permeability-increasing protein (BPI)-type structure, its NH 2 -terminal region lacks structure. Here we found that an 18 amino acid peptide, S18, which corresponded to residues G22-A39 of the SPLUNC1 NH 2 terminus inhibited ENaC activity to a similar degree as full-length SPLUNC1 (∼2.5 fold), while SPLUNC1 protein lacking this region was without effect. S18 did not inhibit the structurally related acid-sensing ion channels, indicating specificity for ENaC. However, S18 preferentially bound to the βENaC subunit in a glycosylation-dependent manner. ENaC hyperactivity is contributory to cystic fibrosis (CF) lung disease. Unlike control, CF human bronchial epithelial cultures (HBECs) where airway surface liquid (ASL) height was abnormally low (4.2 ± 0.6 μm), addition of S18 prevented ENaC-led ASL hyperabsorption and maintained CF ASL height at 7.9 ± 0.6 μm, even in the presence of neutrophil elastase, which is comparable to heights seen in normal HBECs. Our data also indicate that the ENaC inhibitory domain of SPLUNC1 may be cleaved away from the main molecule by neutrophil elastase, suggesting that it may still be active during inflammation or neutrophilia. Furthermore, the robust inhibition of ENaC by the S18 peptide suggests that this peptide may be suitable for treating CF lung disease.

Epithelial sodium channel

Neutrophil elastase

Apical membrane

10.1152/ajplung.00103.2013

Cite

Citations (77)

Crystal Structure of SPLUNC1 Disulfide Mutant M2 (A48C, V253C)

William G. Walton Matthew R. Redinbo

Crystal (programming language)

10.2210/pdb5i7l/pdb

Cite

Citations (0)

Identification of Specific and Nonspecific Inhibitors of Bacillus anthracis Type III Pantothenate Kinase (PanK)

ChemMedChem (2018)

Justin A. Shapiro John Varga Derek Parsonage William G. Walton Matthew R. Redinbo

Abstract Antibiotics with novel mechanisms of action are desperately needed to combat the increasing rates of multidrug‐resistant infections. Bacterial pantothenate kinase (PanK) has emerged as a target of interest to cut off the biosynthesis of coenzyme A. Herein we report the results of an in vitro high‐throughput screen of over 10 000 small molecules against Bacillus anthracis PanK, as well as a follow‐up screen of hits against PanK isolated from Pseudomonas aeruginosa and Burkholderia cenocepacia . Nine hits are structurally categorized and analyzed to set the stage for future drug development.

Bacillus anthracis

Burkholderia cenocepacia

10.1002/cmdc.201800652

Cite

Citations (4)

Substrate preference of Gen endonucleases highlights the importance of branched structures as DNA damage repair intermediates

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2017)

Stephanie P. Bellendir Danielle J. Rognstad Lydia P. Morris Grzegorz Zapotoczny William G. Walton

10.17615/payj-9e79

Cite

Citations (0)