LUBAC

Last updated

Linear ubiquitin chain assembly complex (LUBAC) is a multi-protein complex and the only known E3 ubiquitin ligase able to conjugate ubiquitin in a head-to-tail manner to generate linear (M1-linked) polyubiquitin chains. The complex is currently known to be composed of three proteins: heme-oxidized IRP2 ubiquitin ligase 1 (HOIL-1), HOIL-1-interacting protein (HOIP), and Shank-associated RH domain-interacting protein (SHARPIN) [1] , [2] ,. [3] HOIL-1 and HOIP are both E3 ubiquitin ligases, however, the specific linear ubiquitin-ligating activity is enacted by HOIP. [4] Mice deficient in HOIP are embryonically lethal. [5] Two cases of mutated HOIP have been detected in humans. These patients presented with autoinflammation and immunodeficiency [6] ,. [7] HOIL-1 is required for LUBAC assembly and stability as demonstrated by embryonic lethality in HOIL-1 deficient mice. [8] Recently, it has been noted, that HOIL-1 is also able to catalyze formation of oxyester bonds between the C-terminus of ubiquitin and serine/threonine of substrate protein in TLR signaling. [9] SHARPIN exhibits a significant sequence similarity to HOIL-1 and is important for LUBAC stability. Spontaneous point mutation in the Sharpin gene in mice leads to development of chronic proliferative dermatitis (cpdm) [10] ,. [11] Both HOIL-1 and SHARPIN bind to HOIP through their ubiquitin-like (UBL) domain [1] ,. [2] LUBAC consisting of either HOIP-HOIL-1 or HOIP-SHARPIN is functional in vitro, however the greatest activity of the complex has been observed in the presence of all three components. [2]

LUBAC modulates signaling complexes activating the canonical NF-kB pathway in response to various stimuli (e.g., TNF, IL-1, CD40L) by adding M1-linked polyubiquitin chains to signaling proteins [2] ,. [12] Additionally, LUBAC has been shown to interact with PKC and NLRP3/ASC inflammasome [13] ,. [14]

Antagonistic to LUBAC are deubiquitinases such as OTULIN or CYLD, of which OTULIN is the only deubiquitinase that removes M1-linked ubiquitin linkages exclusively. [15]

LUBAC components have been most widely studied in the context of TNF signaling.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">Parkin (protein)</span>

Parkin is a 465-amino acid residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the PARK2 gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labelled with ubiquitin (Ub) and directed towards degradation in proteasomes or lysosomes. Ubiquitination involves the sequential action of three enzymes. First, an E1 ubiquitin-activating enzyme binds to inactive Ub in eukaryotic cells via a thioester bond and mobilises it in an ATP-dependent process. Ub is then transferred to an E2 ubiquitin-conjugating enzyme before being conjugated to the target protein via an E3 ubiquitin ligase. There exists a multitude of E3 ligases, which differ in structure and substrate specificity to allow selective targeting of proteins to intracellular degradation.

<span class="mw-page-title-main">Deubiquitinating enzyme</span>

Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, ubiquitin isopeptidases, are a large group of proteases that cleave ubiquitin from proteins. Ubiquitin is attached to proteins in order to regulate the degradation of proteins via the proteasome and lysosome; coordinate the cellular localisation of proteins; activate and inactivate proteins; and modulate protein-protein interactions. DUBs can reverse these effects by cleaving the peptide or isopeptide bond between ubiquitin and its substrate protein. In humans there are nearly 100 DUB genes, which can be classified into two main classes: cysteine proteases and metalloproteases. The cysteine proteases comprise ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs) and ovarian tumour proteases (OTU). The metalloprotease group contains only the Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain proteases.

<span class="mw-page-title-main">Endoplasmic-reticulum-associated protein degradation</span>

Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome.

Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process covalently attaches ubiquitin, a short protein of 76 amino acids, to a lysine residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the ATP-dependent unfolding of the target protein that allows passage into the proteasome's 20S core particle, where proteases degrade the target into short peptide fragments for recycling by the cell.

<span class="mw-page-title-main">F-box protein</span> Protein containing at least one F-box domain

F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the 26S proteasome.

<span class="mw-page-title-main">RBX1</span> Protein-coding gene in the species Homo sapiens

RING-box protein 1 is a protein that in humans is encoded by the RBX1 gene.

<span class="mw-page-title-main">BTRC (gene)</span> Protein-coding gene in the species Homo sapiens

F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC gene.

<span class="mw-page-title-main">Ubiquitin C</span> Mammalian protein found in Homo sapiens

Polyubiquitin-C is a protein encoded by the UBC gene in humans. Polyubiquitin-C is one of the sources of ubiquitin, along with UBB, UBA52, and RPS27A.

<span class="mw-page-title-main">UBE2N</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 N is a protein that in humans is encoded by the UBE2N gene.

<span class="mw-page-title-main">CUL2</span> Protein-coding gene in the species Homo sapiens

Cullin-2 is a protein that in humans is encoded by the CUL2 gene.

<span class="mw-page-title-main">UBE2D1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 D1 is a protein that in humans is encoded by the UBE2D1 gene.

<span class="mw-page-title-main">UBE2V2</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 variant 2 is a protein that in humans is encoded by the UBE2V2 gene. Ubiquitin-conjugating enzyme E2 variant proteins constitute a distinct subfamily within the E2 protein family.

<span class="mw-page-title-main">UBE2V1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 variant 1 is a protein that in humans is encoded by the UBE2V1 gene.

<span class="mw-page-title-main">RNF31</span> Protein-coding gene in the species Homo sapiens

RING finger protein 31 is a protein that in humans is encoded by the RNF31 gene.

<span class="mw-page-title-main">RBCK1</span> Protein-coding gene in the species Homo sapiens

RanBP-type and C3HC4-type zinc finger-containing protein 1 is a protein that in humans is encoded by the RBCK1 gene.

<span class="mw-page-title-main">Cullin</span> Hydrophobic scaffold protein

Cullins are a family of hydrophobic scaffold proteins which provide support for ubiquitin ligases (E3). All eukaryotes appear to have cullins. They combine with RING proteins to form Cullin-RING ubiquitin ligases (CRLs) that are highly diverse and play a role in myriad cellular processes, most notably protein degradation by ubiquitination.

<span class="mw-page-title-main">Felix Armin Randow</span>

Felix Armin Randow is a molecular immunologist and tenured group leader at the MRC Laboratory of Molecular Biology in Cambridge. Guided by the importance of cell-autonomous immunity as the sole defender of unicellular organisms, Randow has made contributions to our understanding of host-pathogen interactions. He is an EMBO member, a Wellcome Trust investigator and a Fellow of the Academy of Medical Sciences.

<span class="mw-page-title-main">RNF144A</span> Protein-coding gene in the species Homo sapiens

RNF144A is an E3 ubiquitin ligase belonging to the RING-between RING (RBR) family of ubiquitin ligases, whose specific members have been shown to function as RING-HECT hybrid E3 ligases. RNF144A is most closely related to RNF144B at the protein level, and the two proteins together comprise a subdomain within the RBR family of proteins. The ubiquitin ligase activity of RNF144A catalyzes ubiquitin linkages at the K6-, K11- and K48- positions of ubiquitin in vitro, and is regulated by self-association through its transmembrane domain.

References

  1. 1 2 Kirisako, Takayoshi; Kamei, Kiyoko; Murata, Shigeo; Kato, Michiko; Fukumoto, Hiromi; Kanie, Masato; Sano, Soichi; Tokunaga, Fuminori; Tanaka, Keiji; Iwai, Kazuhiro (2006-10-18). "A ubiquitin ligase complex assembles linear polyubiquitin chains". The EMBO Journal. 25 (20): 4877–4887. doi:10.1038/sj.emboj.7601360. ISSN   0261-4189. PMC   1618115 . PMID   17006537.
  2. 1 2 3 4 Gerlach, Björn; Cordier, Stefanie M.; Schmukle, Anna C.; Emmerich, Christoph H.; Rieser, Eva; Haas, Tobias L.; Webb, Andrew I.; Rickard, James A.; Anderton, Holly; Wong, Wendy W.-L.; Nachbur, Ueli; Gangoda, Lahiru; Warnken, Uwe; Purcell, Anthony W.; Silke, John (March 2011). "Linear ubiquitination prevents inflammation and regulates immune signalling". Nature. 471 (7340): 591–596. doi:10.1038/nature09816. ISSN   1476-4687. PMID   21455173. S2CID   4384869.
  3. ↑ Ikeda, Fumiyo; Deribe, Yonathan Lissanu; Skånland, Sigrid S.; Stieglitz, Benjamin; Grabbe, Caroline; Franz-Wachtel, Mirita; van Wijk, Sjoerd J. L.; Goswami, Panchali; Nagy, Vanja; Terzic, Janos; Tokunaga, Fuminori; Androulidaki, Ariadne; Nakagawa, Tomoko; Pasparakis, Manolis; Iwai, Kazuhiro (March 2011). "SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis". Nature. 471 (7340): 637–641. doi:10.1038/nature09814. ISSN   1476-4687. PMC   3085511 . PMID   21455181.
  4. ↑ Smit, Judith J; Monteferrario, Davide; Noordermeer, Sylvie M; van Dijk, Willem J; van der Reijden, Bert A; Sixma, Titia K (2012-10-03). "The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension: HOIP RBR-LDD module specifies linear ubiquitin chains". The EMBO Journal. 31 (19): 3833–3844. doi:10.1038/emboj.2012.217. PMC   3463842 . PMID   22863777.
  5. ↑ Peltzer, Nieves; Rieser, Eva; Taraborrelli, Lucia; Draber, Peter; Darding, Maurice; Pernaute, Barbara; Shimizu, Yutaka; Sarr, Aida; Draberova, Helena; Montinaro, Antonella; Martinez-Barbera, Juan Pedro; Silke, John; Rodriguez, Tristan A.; Walczak, Henning (2014-10-09). "HOIP Deficiency Causes Embryonic Lethality by Aberrant TNFR1-Mediated Endothelial Cell Death". Cell Reports. 9 (1): 153–165. doi:10.1016/j.celrep.2014.08.066. ISSN   2211-1247. PMID   25284787.
  6. ↑ Boisson, Bertrand; Laplantine, Emmanuel; Dobbs, Kerry; Cobat, Aurélie; Tarantino, Nadine; Hazen, Melissa; Lidov, Hart G.W.; Hopkins, Gregory; Du, Likun; Belkadi, Aziz; Chrabieh, Maya; Itan, Yuval; Picard, Capucine; Fournet, Jean-Christophe; Eibel, Hermann (2015-06-01). "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia". Journal of Experimental Medicine. 212 (6): 939–951. doi:10.1084/jem.20141130. ISSN   1540-9538. PMC   4451137 . PMID   26008899.
  7. ↑ Oda, Hirotsugu; Beck, David B.; Kuehn, Hye Sun; Sampaio Moura, Natalia; Hoffmann, Patrycja; Ibarra, Maria; Stoddard, Jennifer; Tsai, Wanxia Li; Gutierrez-Cruz, Gustavo; Gadina, Massimo; Rosenzweig, Sergio D.; Kastner, Daniel L.; Notarangelo, Luigi D.; Aksentijevich, Ivona (2019-03-18). "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC". Frontiers in Immunology. 10: 479. doi: 10.3389/fimmu.2019.00479 . ISSN   1664-3224. PMC   6431612 . PMID   30936877.
  8. ↑ Peltzer, Nieves; Darding, Maurice; Montinaro, Antonella; Draber, Peter; Draberova, Helena; Kupka, Sebastian; Rieser, Eva; Fisher, Amanda; Hutchinson, Ciaran; Taraborrelli, Lucia; Hartwig, Torsten; Lafont, Elodie; Haas, Tobias L.; Shimizu, Yutaka; Böiers, Charlotta (May 2018). "LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis". Nature. 557 (7703): 112–117. doi:10.1038/s41586-018-0064-8. ISSN   1476-4687. PMC   5947819 . PMID   29695863.
  9. ↑ Kelsall, Ian R.; Zhang, Jiazhen; Knebel, Axel; Arthur, J. Simon C.; Cohen, Philip (2019-07-02). "The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells". Proceedings of the National Academy of Sciences. 116 (27): 13293–13298. doi: 10.1073/pnas.1905873116 . ISSN   0027-8424. PMC   6613137 . PMID   31209050.
  10. ↑ HogenEsch, H.; Torregrosa, S. E.; Boggess, D.; Sundberg, B. A.; Carroll, J.; Sundberg, J. P. (March 2001). "Increased expression of type 2 cytokines in chronic proliferative dermatitis (cpdm) mutant mice and resolution of inflammation following treatment with IL-12". European Journal of Immunology. 31 (3): 734–742. doi:10.1002/1521-4141(200103)31:3<734::aid-immu734>3.0.co;2-9. ISSN   0014-2980. PMID   11241277. S2CID   9944119.
  11. ↑ Seymour, R E; Hasham, M G; Cox, G A; Shultz, L D; HogenEsch, H; Roopenian, D C; Sundberg, J P (July 2007). "Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis". Genes & Immunity. 8 (5): 416–421. doi:10.1038/sj.gene.6364403. ISSN   1466-4879. PMID   17538631. S2CID   27135591.
  12. ↑ Tokunaga, Fuminori; Sakata, Shin-ichi; Saeki, Yasushi; Satomi, Yoshinori; Kirisako, Takayoshi; Kamei, Kiyoko; Nakagawa, Tomoko; Kato, Michiko; Murata, Shigeo; Yamaoka, Shoji; Yamamoto, Masahiro; Akira, Shizuo; Takao, Toshifumi; Tanaka, Keiji; Iwai, Kazuhiro (February 2009). "Involvement of linear polyubiquitylation of NEMO in NF-κB activation". Nature Cell Biology. 11 (2): 123–132. doi:10.1038/ncb1821. ISSN   1465-7392. PMID   19136968. S2CID   23733705.
  13. ↑ Rodgers, Mary A.; Bowman, James W.; Fujita, Hiroaki; Orazio, Nicole; Shi, Mude; Liang, Qiming; Amatya, Rina; Kelly, Thomas J.; Iwai, Kazuhiro; Ting, Jenny; Jung, Jae U. (2014-06-30). "The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation". Journal of Experimental Medicine. 211 (7): 1333–1347. doi:10.1084/jem.20132486. ISSN   1540-9538. PMC   4076580 . PMID   24958845.
  14. ↑ Nakamura, Munehiro; Tokunaga, Fuminori; Sakata, Shin-ichi; Iwai, Kazuhiro (December 2006). "Mutual regulation of conventional protein kinase C and a ubiquitin ligase complex". Biochemical and Biophysical Research Communications. 351 (2): 340–347. doi:10.1016/j.bbrc.2006.09.163. PMID   17069764.
  15. ↑ Keusekotten, Kirstin; Elliott, Paul Ronald; Glockner, Laura; Fiil, Berthe Katrine; Damgaard, Rune Busk; Kulathu, Yogesh; Wauer, Tobias; Hospenthal, Manuela Kathrin; Gyrd-Hansen, Mads; Krappmann, Daniel; Hofmann, Kay; Komander, David (June 2013). "OTULIN Antagonizes LUBAC Signaling by Specifically Hydrolyzing Met1-Linked Polyubiquitin". Cell. 153 (6): 1312–1326. doi:10.1016/j.cell.2013.05.014. PMC   3690481 . PMID   23746843.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.