2014
DOI: 10.1016/j.molcel.2014.03.016
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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 in vivo. The HOIP PUB domain binds to … Show more

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Cited by 166 publications
(236 citation statements)
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References 39 publications
(53 reference statements)
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“…S2B). OTULIN interacts with the PUB domain of HOIP, and their interaction is required for the recruitment of OTULIN to the TNF receptor complex (12). The three mutations do not disrupt the OTULIN interaction with LUBAC, and mutant proteins maintain the intact N-terminal domain necessary for LUBAC interaction ( Fig.…”
Section: Significancementioning
confidence: 97%
“…S2B). OTULIN interacts with the PUB domain of HOIP, and their interaction is required for the recruitment of OTULIN to the TNF receptor complex (12). The three mutations do not disrupt the OTULIN interaction with LUBAC, and mutant proteins maintain the intact N-terminal domain necessary for LUBAC interaction ( Fig.…”
Section: Significancementioning
confidence: 97%
“…Thereby OTULIN can only cleave peptide bonds present in M1-linked chains (Keusekotten et al, 2013;Rivkin et al, 2013). This M1-linked-chain-specific OTULIN interacts with HOIP, the catalytic core subunit of LUBAC, forming a functional complex that regulates the production of linear chains (Elliott et al, 2014;Schaeffer et al, 2014). Besides OTULIN, USP10 (Niu et al, 2013) and the cylindromatosis tumor suppressor (CYLD) have been shown to counteract LUBAC-mediated linear ubiquitylation.…”
Section: M1 Linkages -Key Regulator In Nf-κb Signalingmentioning
confidence: 99%
“…Three PUB-domain containing proteins have been described so far in humans and all interact with the p97 C-terminal tail: PNGase (peptide N-glycanase) [85,86], which is involved in the deglycosylation of misfolded glycoproteins [87], the UBX protein UBXD1 [68,85,88], and HOIP (HOIL-1-interacting protein) [89][90][91], the catalytic subunit of the E3 ubiquitin ligase LUBAC, which catalyzes the assembly of linear ubiquitin chains [92]. Molecular insights into the interaction of the PUB domain with p97 were revealed by crystal structures of the PNGase and HOIP PUB domains in complex with peptides comprising the five and four, respectively, C-terminal residues of p97 called PIM (PUB Interacting Motif) [86,91] (Fig. 2D).…”
Section: The Pub Domainmentioning
confidence: 99%
“…The PUB-PIM complex is stabilized by a combination of hydrophobic and electrostatic interactions, with a key interaction mediated by insertion of the hydrophobic side chain of Leu804 and the aromatic side chain of Tyr805 of p97 into a hydrophobic pocket of the PUB domain called the U-Y pocket [91]. Interestingly, phosphorylation of the strictly conserved tyrosine residue within the PIM (Tyr805 in p97) completely blocks the interaction of p97 with the PUB domain and with the PUL domain of Ufd3 (see below) [86,90,91,93]. Thus, tyrosine phosphorylation appears to be a conserved mechanism to control protein-protein interactions of the C-terminal tail of p97.…”
Section: The Pub Domainmentioning
confidence: 99%