@article{990d1f7e297d453e82b6c20b7a1a09e0,
title = "Binding of OTULIN to the PUB Domain of HOIP Controls NF-κB Signaling",
abstract = "Linear ubiquitin chains are implicated in the regulation of the NF-κB pathway, immunity, and inflammation. They are synthesized by the LUBAC complex containing the catalytic subunit HOIL-1-interacting protein (HOIP) and are disassembled by the linear ubiquitin-specific deubiquitinase OTULIN. Little is known about the regulation of these opposing activities. Here we demonstrate that HOIP and OTULIN interact and act as a bimolecular editing pair for linear ubiquitin signals invivo. The HOIP PUB domain binds to the PUB interacting motif (PIM) of OTULIN and the chaperone VCP/p97. Structural studies revealed the basis of high-affinity interaction with the OTULIN PIM. The conserved Tyr56 of OTULIN makes critical contacts with the HOIP PUB domain, and its phosphorylation negatively regulates this interaction. Functionally, HOIP binding to OTULIN is required for the recruitment of OTULIN to the TNF receptor complex and to counteract HOIP-dependent activation of the NF-κB pathway.",
author = "Veronique Schaeffer and Masato Akutsu and Olma, {Michael H.} and Gomes, {Ligia C.} and Masato Kawasaki and Ivan Dikic",
note = "Funding Information: We are thankful to Fernando Bazan for the bioinformatics analysis of the HOIP PUB domain; Jan Heering for help with ITC measurements; Alexander Buchberger for p97 and UBXD1 constructs; David McEwan, Anja Bremm, and Jaime Lopez-Mosqueda for critical reading of the manuscript; Masuda Sader for help with protein purifications; and all members of the Dikic lab for discussions and constructive comments. Crystallographic data were collected at KEK, photon factory, beamline BL1A and BL17 and DIAMOND light source, beamline I03. The work was supported by the Cluster of Excellence “Macromolecular Complexes” of the Goethe University Frankfurt (EXC115), the LOEWE funded OSF network, the LOEWE Gene and Cell Therapy Center, and the European Research Council/ERC grant agreement n° [250241-LineUb] to I.D. The research leading to these results received also funding from the European Union Seventh Framework Programme (FP7/2007-2013) PRIMES project under grant agreement number FP7-HEALTH-2010-278568 and from the FSP SPP1365. ",
year = "2014",
month = may,
day = "8",
doi = "10.1016/j.molcel.2014.03.016",
language = "English",
volume = "54",
pages = "349--361",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",
}