Control of Colon Cancer Progression by the Colon Microbiome
Abstract
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 TAB2/3.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2015
- Accession Number
- AD1018895
Entities
People
- Frank Iii J. Rauscher
Organizations
- Wistar Institute