Ubiquitin Signaling and Bacterial Effector Proteins
EMSL Project ID
40116
Abstract
In plants and animals post-translational modification of proteins by ubiquitin (Ub) is a regulatory process that impacts nearly every aspect of eukaryotic cell biology. Diverse pathways including, but not limited to, cell-cycle progression, innate immune responses, DNA repair, and endocytosis all rely on regulated modification of target proteins by Ub. It is not surprising that aberrations in Ub signaling pathways are implicated in the etiology and progression of numerous diseases including tumorigenesis and neurodegenerative diseases and infection. Various strains of gram-negative bacteria use macromolecular transport machinery termed Type III Secretion Systems to introduce proteins directly into the cytosol of host cells to pave the way for bacterial invasion and replication. The invading pathogen can introduce as many as 30 to 40 different effector proteins into the plant or animal host at various stages of invasion. A large percentage of these proteins have been found to exploit, interfere with, or hijack eukaryotic signaling pathways to promote bacterial uptake into the host, modulate the immune response, and enhance infectivity. This proposal is part of our overall effort designed to identify protein interactions fundamental to Ub transfer reactions, to identify level the networks of protein interactions that govern assembly of active ubiquitin-ligase complexes and how these interactions influence the products of Ub transfer reactions. Unique aspects of our approach exploit recent discoveries of effector proteins found in strains of gram-negative bacteria that directly interact with, interfere with, or hijack eukaryotic signaling pathways. The interface between prokaryotic and eukaryotic organisms provides a means to understand not only bacterial pathogenesis, but also understand critical eukaryotic signaling systems.
Project Details
Project type
Large-Scale EMSL Research
Start Date
2010-10-01
End Date
2013-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
LaRock DL, PS Brzovic, I Levin, MP Blanc, and SI Miller. 2012. "A Salmonella typhimurium-translocated Glycerophospholipid:Cholesterol Acyltransferase Promotes Virulence by Binding to the RhoA Protein Switch Regions." Journal of Biological Chemistry 287(35):29654-29663. doi:10.1074/jbc.M112.363598
Pruneda JN, FD Smith, A Daurie, DL Swaney, J Villen, JD Scott, AW Stadnyk, I Le Trong, RE Stenkamp, RE Klevit, JR Rohde, and PS Brzovic. 2014. "E2~Ub Conjugates Regulate the Kinase Activity of Shigella Effector OspG During Pathogenesis." EMBO Journal 33:437-449. doi:10.1002/embj.201386386
Pruneda JN, KE Stoll, LJ Bolton, PS Brzovic, and RE Klevit. 2011. "Ubiquitin in Motion: Structural Studies of the Ubiquitin-Conjugating Enzyme?Ubiquitin Conjugate." Biochemistry 50(10):1624-1633. doi:10.1021/bi101913m
Pruneda JN, PJ Littlefield, SE Soss, KA Nordquist, PS Brzovic, and RE Klevit. 2012. "Structure of an E3:E2~-Ub Complex Reveals an Allosteric Mechanism Shared among RING/U-box Ligases." Molecular Cell 47(6):933–942. doi:10.1016/j.molcel.2012.07.001