Molecular Basis and Regulation of OTULIN-LUBAC Interaction

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Apr 15

PMID 24726323

Citations 110

Authors

Paul R Elliott

Sofie V Nielsen

Paola Marco-Casanova

Berthe Katrine Fiil

Kirstin Keusekotten

Niels Mailand

Stefan M V Freund

Mads Gyrd-Hansen

David Komander

Affiliations

Soon will be listed here.

Abstract

The linear ubiquitin (Ub) chain assembly complex (LUBAC) generates Met1-linked "linear" Ub chains that regulate the activation of the nuclear factor κB (NFκB) transcription factor and other processes. We recently discovered OTULIN as a deubiquitinase that specifically cleaves Met1-linked polyUb. Now, we show that OTULIN binds via a conserved PUB-interacting motif (PIM) to the PUB domain of the LUBAC component HOIP. Crystal structures and nuclear magnetic resonance experiments reveal the molecular basis for the high-affinity interaction and explain why OTULIN binds the HOIP PUB domain specifically. Analysis of LUBAC-induced NFκB signaling suggests that OTULIN needs to be present on LUBAC in order to restrict Met1-polyUb signaling. Moreover, LUBAC-OTULIN complex formation is regulated by OTULIN phosphorylation in the PIM. Phosphorylation of OTULIN prevents HOIP binding, whereas unphosphorylated OTULIN is part of the endogenous LUBAC complex. Our work exemplifies how coordination of ubiquitin assembly and disassembly activities in protein complexes regulates individual Ub linkage types.

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References

Stieglitz B, Haire L, Dikic I, Rittinger K . Structural analysis of SHARPIN, a subunit of a large multi-protein E3 ubiquitin ligase, reveals a novel dimerization function for the pleckstrin homology superfold. J Biol Chem. 2012; 287(25):20823-9. PMC: 3375506. DOI: 10.1074/jbc.M112.359547. View

Allen M, Buchberger A, Bycroft M . The PUB domain functions as a p97 binding module in human peptide N-glycanase. J Biol Chem. 2006; 281(35):25502-8. DOI: 10.1074/jbc.M601173200. View

Gerlach B, Cordier S, Schmukle A, Emmerich C, Rieser E, Haas T . Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011; 471(7340):591-6. DOI: 10.1038/nature09816. View

Kamiya Y, Uekusa Y, Sumiyoshi A, Sasakawa H, Hirao T, Suzuki T . NMR characterization of the interaction between the PUB domain of peptide:N-glycanase and ubiquitin-like domain of HR23. FEBS Lett. 2012; 586(8):1141-6. DOI: 10.1016/j.febslet.2012.03.027. View

Fiil B, Damgaard R, Wagner S, Keusekotten K, Fritsch M, Bekker-Jensen S . OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. Mol Cell. 2013; 50(6):818-830. PMC: 4194427. DOI: 10.1016/j.molcel.2013.06.004. View

Yagi H, Ishimoto K, Hiromoto T, Fujita H, Mizushima T, Uekusa Y . A non-canonical UBA-UBL interaction forms the linear-ubiquitin-chain assembly complex. EMBO Rep. 2012; 13(5):462-8. PMC: 3343348. DOI: 10.1038/embor.2012.24. View

Emmerich C, Ordureau A, Strickson S, Arthur J, Pedrioli P, Komander D . Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. Proc Natl Acad Sci U S A. 2013; 110(38):15247-52. PMC: 3780889. DOI: 10.1073/pnas.1314715110. View

Kern M, Fernandez-Saiz V, Schafer Z, Buchberger A . UBXD1 binds p97 through two independent binding sites. Biochem Biophys Res Commun. 2009; 380(2):303-7. DOI: 10.1016/j.bbrc.2009.01.076. View

Stieglitz B, Morris-Davies A, Koliopoulos M, Christodoulou E, Rittinger K . LUBAC synthesizes linear ubiquitin chains via a thioester intermediate. EMBO Rep. 2012; 13(9):840-6. PMC: 3432797. DOI: 10.1038/embor.2012.105. View

10.

Mevissen T, Hospenthal M, Geurink P, Elliott P, Akutsu M, Arnaudo N . OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis. Cell. 2013; 154(1):169-84. PMC: 3705208. DOI: 10.1016/j.cell.2013.05.046. View

11.

Walczak H, Iwai K, Dikic I . Generation and physiological roles of linear ubiquitin chains. BMC Biol. 2012; 10:23. PMC: 3305636. DOI: 10.1186/1741-7007-10-23. View

12.

Ikeda F, Deribe Y, Skanland S, Stieglitz B, Grabbe C, Franz-Wachtel M . SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature. 2011; 471(7340):637-41. PMC: 3085511. DOI: 10.1038/nature09814. View

13.

Solyom Z, Schwarten M, Geist L, Konrat R, Willbold D, Brutscher B . BEST-TROSY experiments for time-efficient sequential resonance assignment of large disordered proteins. J Biomol NMR. 2013; 55(4):311-21. DOI: 10.1007/s10858-013-9715-0. View

14.

Smit J, Monteferrario D, Noordermeer S, van Dijk W, van der Reijden B, Sixma T . The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension. EMBO J. 2012; 31(19):3833-44. PMC: 3463842. DOI: 10.1038/emboj.2012.217. View

15.

Chen Z, Sun L . Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell. 2009; 33(3):275-86. DOI: 10.1016/j.molcel.2009.01.014. View

16.

Stieglitz B, Rana R, Koliopoulos M, Morris-Davies A, Schaeffer V, Christodoulou E . Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature. 2013; 503(7476):422-426. PMC: 3838313. DOI: 10.1038/nature12638. View

17.

Fu B, Li S, Wang L, Berman M, Dorf M . The ubiquitin conjugating enzyme UBE2L3 regulates TNFα-induced linear ubiquitination. Cell Res. 2013; 24(3):376-9. PMC: 3945881. DOI: 10.1038/cr.2013.133. View

18.

Rivkin E, Almeida S, Ceccarelli D, Juang Y, MacLean T, Srikumar T . The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis. Nature. 2013; 498(7454):318-24. PMC: 4931916. DOI: 10.1038/nature12296. View

19.

Li G, Zhao G, Schindelin H, Lennarz W . Tyrosine phosphorylation of ATPase p97 regulates its activity during ERAD. Biochem Biophys Res Commun. 2008; 375(2):247-51. DOI: 10.1016/j.bbrc.2008.08.018. View

20.

Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S . SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature. 2011; 471(7340):633-6. DOI: 10.1038/nature09815. View