Specific recognition of linear ubiquitin chains by the Npl4 zinc finger (NZF) domain of the HOIL-1L subunit of the linear ubiquitin chain assembly complex

Sato, Yusuke; Fujita, Hiroaki; Yoshikawa, Azusa; Yamashita, Masami; Yamagata, Atsushi; Kaiser, Stephen E.; Iwaï, Kazuhiro; Fukai, Shuya

doi:10.1073/pnas.1109088108

Cited by 104 publications

(164 citation statements)

References 32 publications

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“…A subset of UBDs is able to specifically recognize a particular poly-Ub topology and this is typically achieved by simultaneously binding to two neighboring Ub within the chain that shows a linkage-specific conformation. For example, the UBAN domain of NEMO and the NZF domain of HOIL-1L specifically recognize linear (Met1-linked) Ub chains by making contacts to a surface on one Ub moiety and the canonical hydrophobic surface on the other Ub (Rahighi et al 2009;Sato et al 2011). The NZF domains of TAB2 and TAB3 also simultaneously interact with two neighboring Ub moieties, but can do so only when linked via a K63 linkage (Kulathu et al 2009).…”

Section: Ubiquitin-dependent Sorting In Endocytosismentioning

confidence: 99%

Ubiquitin-Dependent Sorting in Endocytosis

Piper

Đikić

Lukacs

2014

Cold Spring Harbor Perspectives in Biology

193

176

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When ubiquitin (Ub) is attached to membrane proteins on the plasma membrane, it directs them through a series of sorting steps that culminate in their delivery to the lumen of the lysosome where they undergo complete proteolysis. Ubiquitin is recognized by a series of complexes that operate at a number of vesicle transport steps. Ubiquitin serves as a sorting signal for internalization at the plasma membrane and is the major signal for incorporation into intraluminal vesicles of multivesicular late endosomes. The sorting machineries that catalyze these steps can bind Ub via a variety of Ub-binding domains. At the same time, many of these complexes are themselves ubiquitinated, thus providing a plethora of potential mechanisms to regulate their activity. Here we provide an overview of how membrane proteins are selected for ubiquitination and deubiquitination within the endocytic pathway and how that ubiquitin signal is interpreted by endocytic sorting machineries. HOW PROTEINS ARE SELECTED FOR UBIQUITINATIONU biquitin (Ub) is covalently attached to substrate proteins by the concerted action of E2-conjugating enzymes and E3 ligases (Varshavsky 2012). Most of the specificity and regulation of ubiquitination is at the level of the E3 ligases, which vastly outnumber the E2-conjugating enzymes. Ubiquitination results from the transfer of Ub, held either by the E2 or in some cases by the E3 as a high-energy thioester bond, onto a substrate protein, typically on the terminal amide of a substrate acceptor lysine side chain. Owing to the intense interest in the ubiquitination system, many of the simple rules and distinctions concerning different types of ligases, their specificity for forming particular polyUb chains, and even the kinds of residues in substrate proteins that can be ubiquitin modified, have been blurred with the discovery of mixed poly-Ub chains, new enzymatic mechanisms for Ub transfer, and ubiquitination of nonlysine residues (Kulathu and Komander 2012;Wenzel and Klevit 2012;McDowell and Philpott 2013). Nonetheless, in basic terms, Ub ligases function as platforms that coordinate substrate recognition with Ub transfer as well as configuring poly-Ub chain topology by the E2-conjugating enzyme. Substrates can be bound directly by the E3 ligase or by adaptor proteins that in turn bind to ligases, and selecEditors:

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Section: Ubiquitin-dependent Sorting In Endocytosismentioning

confidence: 99%

Ubiquitin-Dependent Sorting in Endocytosis

Piper

Đikić

Lukacs

2014

Cold Spring Harbor Perspectives in Biology

193

176

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“…The ubiquitin-like (UBL) domain of HOIL-1L and the ubiquitin-associated domain (UBA) of HOIP are necessary for LUBAC formation, whereas the two RING domains of HOIP are required for LUBAC's linear polyubiquitination activity (35). Furthermore, HOIL-1L Npl4 zinc finger domain (NZF) is required for specific recognition of linear ubiquitin chains (36). Interestingly, neither the overexpression of HOIL-1LDUBL nor HOIL-1LDNZF prevented the interaction between PKCz and HOIL-1L ( Figure 3B).…”

Section: Hoil-1l Ubiquitinates Pkcz Independently Of Lubac During Hypmentioning

confidence: 99%

HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

Queisser

Dada

Deiss-Yehiely

et al. 2014

Am J Respir Crit Care Med

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Rationale: Protein kinase C zeta (PKCz) has been reported to act as a tumor suppressor. Deletion of PKCz in experimental cancer models has been shown to increase tumor growth. However, the mechanisms of PKCz down-regulation in cancerous cells have not been previously described.Objectives: To determine the molecular mechanisms that lead to decreased PKCz expression and thus increased survival in cancer cells and tumor growth.Methods: The levels of expression of heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L), HOIL-1-interacting protein (HOIP), Shank-associated RH domain-interacting protein (SHARPIN), and PKCz were analyzed by Western blot and/or quantitative real-time polymerase chain reaction in different cell lines. Coimmunoprecipitation experiments were used to demonstrate the interaction between HOIL-1L and PKCz. Ubiquitination was measured in an in vitro ubiquitination assay and by Western blot with specific antibodies. The role of hypoxia-inducible factor (HIF) was determined by gain/loss-of-function experiments. The effect of HOIL-1L expression on cell death was investigated using RNA interference approaches in vitro and on tumor growth in mice models. Increased HOIL-1L and decreased PKCz expression was assessed in lung adenocarcinoma and glioblastoma multiforme and documented in several other cancer types by oncogenomic analysis. Measurements and Main Results:Hypoxia is a hallmark of rapidly growing solid tumors. We found that during hypoxia, PKCz is ubiquitinated and degraded via the ubiquitin ligase HOIL-1L, a component of the linear ubiquitin chain assembly complex (LUBAC). In vitro ubiquitination assays indicate that HOIL-1L ubiquitinates PKCz at Lys-48, targeting it for proteasomal degradation. In a xenograft tumor model and lung cancer model, we found that silencing of HOIL-1L increased the abundance of PKCz and decreased the size of tumors, suggesting that lower levels of HOIL-1L promote survival. Indeed, mRNA transcript levels of HOIL-1L were elevated in tumor of patients with lung adenocarcinoma, and in a lung adenocarcinoma tissue microarray the levels of HOIL-1L were associated with high-grade tumors. Moreover, we found that HOIL-1L expression was regulated by HIFs. Interestingly, the actions of HOIL-1L were independent of LUBAC.Conclusions: These data provide first evidence of a mechanism of cancer cell adaptation to hypoxia where HIFs regulate HOIL-1L, which targets PKCz for degradation to promote tumor survival. We provided a proof of concept that silencing of HOIL-1L impairs lung tumor growth and that HOIL-1L expression predicts survival rate in cancer patients suggesting that HOIL-1L is an attractive target for cancer therapy.

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“…HOIP also carries two NZF domains, NZF1 and NZF2 (8). Since the NZF domains serve as the ubiquitin-binding modules, LUBAC seems to possess multiple ubiquitin-binding activities (19,21). Previous reports show that loss of any of the three LUBAC subunits results in distinct phenotypes in mice and humans, indicating the differential roles of each subunit in LUBAC functions.…”

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confidence: 99%

Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection

Shimizu

Fujita

Sasaki

et al. 2016

Molecular and Cellular Biology

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The linear ubiquitin chain assembly complex (LUBAC) participates in NF-κB activation and cell death protection. Loss of any of the three LUBAC subunits (catalytic HOIP, accessory HOIL-1L, or accessory SHARPIN subunit) leads to distinct phenotypes in mice and human. cpdm mice (chronic proliferative dermatitis in mice [cpdm]) that lack SHARPIN exhibit chronic inflammatory phenotypes, whereas HOIL-1L knockout mice exhibit no overt phenotypes, despite sharing highly homologous ubiquitin-like (UBL) and Npl4 zinc finger (NZF) domains. Here, we intercrossed mice lacking HOIL-1L and SHARPIN and found that reduction of HOIL-1L in cpdm mice exacerbated inflammatory phenotypes without affecting characteristic features of cpdm disease, whereas reduction of SHARPIN in HOIL-1L knockout mice provoked no overt phenotypes. Hence, loss of SHARPIN and reduction of LUBAC triggers cpdm phenotypes. We found that the NZF domain of SHARPIN, but not that of HOIL-1L, is critical for effective protection from programmed cell death by enhancing the recruitment of LUBAC to the activated TNFR complex. The binding activity to K63-linked ubiquitin chains that the NZF domain of SHARPIN, but not that of HOIL-1L, possesses appears to be involved in the recruitment. Thus, selective recognition of ubiquitin chains by NZFs in LUBAC underlies the regulation of LUBAC function.

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Specific recognition of linear ubiquitin chains by the Npl4 zinc finger (NZF) domain of the HOIL-1L subunit of the linear ubiquitin chain assembly complex

Cited by 104 publications

References 32 publications

Ubiquitin-Dependent Sorting in Endocytosis

Ubiquitin-Dependent Sorting in Endocytosis

HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection

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