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Control of Colon Cancer Progression by the Colon Microbiome

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Technical Report,15 Jul 2014,14 Jul 2015

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The Wistar Institute of Anatomy and Biology Philadelphia United States

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This Research Project was funded to define the roles of bacterial pathogen proteins which modify host proteins by post-translational modification. We have made great progress in accomplishing all of the AIMS of this project. The NF-B pathwayis most critical for immune defense against infection, thereby frequently targeted by bacterial virulence effectors. NleE, aneffector from EPEC and related enteric bacteria, is a SAM-dependent methyltransferase that blocks host NF-B-mediatedinflammation. We have solved the crystal structure of NleE-SAM complex, which reveals a methyltransferase fold differentfrom those of known methyltransferases. We further identify a new NleE substrate ZRANB3, which has well defined roles inPCNA binding and remodeling of stalled replication forks at sites of DNA damage. NleE-catalyzed cysteine methylation of theZRANB3-NZF domain also abolishes its K63-linked ubiquitin chain-binding activity, a key modification of PCNA which initiatesrepair. Specific inactivation of the NZF domain in ZRANB3 by NleE, and hence its DNA repair functions suggests a novel andunexpected link between EPEC infection, virulence proteins and genome integrity. We have also discovered a new NleE substrate ZRANB1 Trabid1 , which contains three target zinc fingers and differentially methylates these three fingers tomodulate binding to mixed ubiquitin linked chains. Trabid1 functions in the NF-kB pathway in innate immunity like TAB23.

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