TY - JOUR
T1 - The Molecular Basis for Ubiquitin and Ubiquitin-like Specificities in Bacterial Effector Proteases
AU - Pruneda, Jonathan N.
AU - Durkin, Charlotte H.
AU - Geurink, Paul P.
AU - Ovaa, Huib
AU - Santhanam, Balaji
AU - Holden, David W.
AU - Komander, David
N1 - Funding Information:
We would like to thank R. Mittal (MRC Laboratory of Molecular Biology), R. Hay (University of Dundee), B. Schulman (St. Jude Children’s Research Hospital), and A. Canto-Pastor and D. Baulcombe (University of Cambridge) for providing reagents, and the beamline staff at ESRF ID23-1 and DLS I03, I04, and I04-1 for their assistance. Access to DLS was supported, in part, by the EU FP7 infrastructure grant BIOSTRUCT-X (contract no. 283570). The graphical abstract uses images adapted from Servier Medical Art. We also thank members of the D.K. lab for reagents and advice and K. Swatek for critical comments on the manuscript. Work in the D.K. lab was funded by the Medical Research Council (U105192732), the European Research Council (309756), and the Lister Institute for Preventive Medicine. J.N.P was supported by an EMBO Long-term Fellowship. Work in the H.O. lab was supported by a Netherlands Organization for Scientific Research VICI grant (724.013.002) and the European Research Council (281699). C.H.D. and D.W.H. were funded by a Medical Research Council grant (WMNM_P45464) (to D.W.H.). B.S. was funded by the Medical Research Council (U105185859). D.K. and H.O. are part of the DUB Alliance that includes Cancer Research Technology and FORMA Therapeutics. H.O. is founder and shareholder of the company UbiQ that markets reagents in the ubiquitin field.
PY - 2016/7/21
Y1 - 2016/7/21
N2 - Pathogenic bacteria rely on secreted effector proteins to manipulate host signaling pathways, often in creative ways. CE clan proteases, specific hydrolases for ubiquitin-like modifications (SUMO and NEDD8) in eukaryotes, reportedly serve as bacterial effector proteins with deSUMOylase, deubiquitinase, or, even, acetyltransferase activities. Here, we characterize bacterial CE protease activities, revealing K63-linkage-specific deubiquitinases in human pathogens, such as Salmonella, Escherichia, and Shigella, as well as ubiquitin/ubiquitin-like cross-reactive enzymes in Chlamydia, Rickettsia, and Xanthomonas. Five crystal structures, including ubiquitin/ubiquitin-like complexes, explain substrate specificities and redefine relationships across the CE clan. Importantly, this work identifies novel family members and provides key discoveries among previously reported effectors, such as the unexpected deubiquitinase activity in Xanthomonas XopD, contributed by an unstructured ubiquitin binding region. Furthermore, accessory domains regulate properties such as subcellular localization, as exemplified by a ubiquitin-binding domain in Salmonella Typhimurium SseL. Our work both highlights and explains the functional adaptations observed among diverse CE clan proteins.
AB - Pathogenic bacteria rely on secreted effector proteins to manipulate host signaling pathways, often in creative ways. CE clan proteases, specific hydrolases for ubiquitin-like modifications (SUMO and NEDD8) in eukaryotes, reportedly serve as bacterial effector proteins with deSUMOylase, deubiquitinase, or, even, acetyltransferase activities. Here, we characterize bacterial CE protease activities, revealing K63-linkage-specific deubiquitinases in human pathogens, such as Salmonella, Escherichia, and Shigella, as well as ubiquitin/ubiquitin-like cross-reactive enzymes in Chlamydia, Rickettsia, and Xanthomonas. Five crystal structures, including ubiquitin/ubiquitin-like complexes, explain substrate specificities and redefine relationships across the CE clan. Importantly, this work identifies novel family members and provides key discoveries among previously reported effectors, such as the unexpected deubiquitinase activity in Xanthomonas XopD, contributed by an unstructured ubiquitin binding region. Furthermore, accessory domains regulate properties such as subcellular localization, as exemplified by a ubiquitin-binding domain in Salmonella Typhimurium SseL. Our work both highlights and explains the functional adaptations observed among diverse CE clan proteins.
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U2 - 10.1016/j.molcel.2016.06.015
DO - 10.1016/j.molcel.2016.06.015
M3 - Article
C2 - 27425412
AN - SCOPUS:84978880194
VL - 63
SP - 261
EP - 276
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 2
ER -