A ubiquitin ligase complex assembles linear polyubiquitin chains

Kirisako, Takayoshi; Kamei, Kaeko; Murata, Shigeo; Kato, Michiko; Fukumoto, Hiromi; Kanie, Masato; Sano, Soichi; Tokunaga, Fuminori; Tanaka, Keiji; Iwaï, Kazuhiro

doi:10.1038/sj.emboj.7601360

Cited by 710 publications

(835 citation statements)

References 44 publications

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“…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.…”

Section: The Pub Domainmentioning

confidence: 99%

Control of p97 function by cofactor binding

2015

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Edited by Wilhelm JustKeywords: ATPases Associated with diverse cellular Activities p47 UFD1-NPL4 UBXD1 Inclusion Body Myopathy with Pagets disease of the bone and Fronto-temporal Dementia a b s t r a c t p97 (also known as Cdc48, Ter94, and VCP) is an essential, abundant and highly conserved ATPase driving the turnover of ubiquitylated proteins in eukaryotes. Even though p97 is involved in highly diverse cellular pathways and processes, it exhibits hardly any substrate specificity on its own. Instead, it relies on a large number of regulatory cofactors controlling substrate specificity and turnover. The complexity as well as temporal and spatial regulation of the interactions between p97 and its cofactors is only beginning to be understood at the molecular level. Here, we give an overview on the structural framework of p97 interactions with its cofactors, the emerging principles underlying the assembly of complexes with different cofactors, and the pathogenic effects of disease-associated p97 mutations on cofactor binding.

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Section: The Pub Domainmentioning

confidence: 99%

Control of p97 function by cofactor binding

2015

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“…As shown by a recent study, methylation of a Cys residue in NZF domain of either TAB2 or TAB3 disrupts polyubiquitin recognition and blocks NF-jB signaling pathway [49]. Another example is HOIL-1L protein, which is a component of the linear ubiquitin chain assembly complex (LUBAC) [9]. HOIL-1L recognizes Met1-linked ubiquitin chains through its NZF domain.…”

Section: Multiple Ubiquitin-binding By a Single Ubdmentioning

confidence: 99%

Selectivity of the ubiquitin‐binding modules

Rahighi

Đikić

2012

FEBS Letters

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a b s t r a c tUbiquitin-binding modules are constituents of cellular proteins that mediate the effects of ubiquitylation by making transient, non-covalent interactions with ubiquitin molecules. While some ubiquitin-binding modules bind single ubiquitin moieties, others are selective for specific ubiquitin chains of different linkage types and lengths. In recent years, functions of ubiquitin chains that are polymerized through their Lys or N-terminal Met (i.e. linear chains) residues have been linked to a variety of cellular processes. Selectivity of ubiquitin-binding modules for different ubiquitin chain types appears as a key to the distinct regulatory consequences during protein quality control pathways, receptor endocytosis, gene transcription, signaling via the NF-jB pathway, and autophagy.

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“…We thus hypothesized that the ubiquitin ligase complex recognizes ubiquitin as a substrate and conjugates ubiquitin onto it to generate polyubiquitin chains. Further analyses revealed that the HOIL-1L-HOIP complex indeed generates linear polyubiquitin chains exclusively [ 4 ].…”

Section: The Linear Ubiquitin Chains and Their Roles In Nf-κb Activationmentioning

confidence: 99%

“…We have identifi ed a new type of polyubiquitin chain, the linear polyubiquitin chain, in which the carboxyl group of a ubiquitin monomer forms a peptide bond with an N-terminal Met residue of another ubiquitin molecule (Fig. 1 ) [ 4 ]. We have also identifi ed the ubiquitin ligase Fig.…”

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confidence: 99%

“…Conjugated ubiquitins are cleaved by deubiquitinating enzymes (DUBs). The function of conjugated proteins is modulated via specifi c recognition of conjugated polyubiquitin chains complex that specifi cally generates linear polyubiquitin chains and named it as the linear ubiquitin chain assembly complex (LUBAC) [ 4 ]. Further analysis has revealed that linear polyubiquitination is involved in NF-κB activation [ 5 ].…”

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Linear Polyubiquitination: A Crucial Regulator of NF-κB Activation

Iwaï

2015

Innovative Medicine

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NF-κB is a transcription factor known to be involved in pleomorphic biological phenomena such as infl ammation and immune responses. Abnormal activation of NF-κB has been reported in many pathological conditions, including malignant tumors. Therefore, the NF-κB activation pathway has been extensively studied and involvement of the ubiquitin conjugation system in the NF-κB activation pathways has been revealed. Although the ubiquitin conjugation system was discovered as a part of a protein degradation pathway, non-degradable roles of the ubiquitin system have been revealed recently. Several types of polyubiquitin chains exist in cells and the type of chain seems to determine how ubiquitinated proteins are regulated. We have identifi ed that a new type of polyubiquitin chain, the linear polyubiquitin chain, plays a crucial role in regulating the NF-κB activation pathway in non-degradable manner. In this chapter, the discovery, roles in NF-κB activation, and involvement in the pathogenesis of cancers of linear ubiquitination will be discussed. Keywords NF-κB • Ubiquitin • LUBAC • Linear ubiquitin chain • cpdm • B cell lymphoma The Ubiquitin Conjugation SystemThe ubiquitin system, which is one of the most extensively studied post-translational protein modifi cation systems, has been identifi ed as part of an energy-dependent degradation system [ 1 ]. Ubiquitin is a protein-based modifi er composed of 76 amino acids. Through the function of three enzymes called the ubiquitin-activating enzyme (E1), the ubiquitin conjugating enzyme (E2) and the ubiquitin ligase (E3), ubiquitin is conjugated to the substrate proteins that are recognized by E3s. Ubiquitin is added onto ubiquitin pre-conjugated to the substrates to generate polyubiquitin chains-polymer of ubiquitin. The proteasome recognizes the polyubiquitin chains

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A ubiquitin ligase complex assembles linear polyubiquitin chains

Cited by 710 publications

References 44 publications

Control of p97 function by cofactor binding

Control of p97 function by cofactor binding

Selectivity of the ubiquitin‐binding modules

Linear Polyubiquitination: A Crucial Regulator of NF-κB Activation

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