Ubiquitin thioesterase otulin

Definition:

Deubiquitinase that specifically removes linear ('Met-1'-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response. Required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling together with the LUBAC complex. Acts as a negative regulator of NF-kappa-B by regulating the activity of the LUBAC complex. OTULIN function is mainly restricted to homeostasis of the LUBAC complex: acts by removing 'Met-1'-linked autoubiquitination of the LUBAC complex, thereby preventing inactivation of the LUBAC complex. Acts as a key negative regulator of inflammation by restricting spontaneous inflammation and maintaining immune homeostasis. In myeloid cell, required to prevent unwarranted secretion of cytokines leading to inflammation and autoimmunity by restricting linear polyubiquitin formation. Plays a role in innate immune response by restricting linear polyubiquitin formation on LUBAC complex in response to NOD2 stimulation, probably to limit NOD2-dependent pro-inflammatory signaling.

References:

[1]. Paul R Elliott, et al. Molecular basis and regulation of OTULIN-LUBAC interaction. Mol Cell. 2014 May 8;54(3):335-48. [Content Brief]

[2]. Elena Rivkin, et al. The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis. Nature. 2013 Jun 20;498(7454):318-24. [Content Brief]

[3]. Veronique Schaeffer, et al. Binding of OTULIN to the PUB domain of HOIP controls NF-κB signaling. Mol Cell. 2014 May 8;54(3):349-61. [Content Brief]

[4]. Berthe Katrine Fiil, et al. OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. Mol Cell. 2013 Jun 27;50(6):818-830. [Content Brief]

[5]. Kirstin Keusekotten, et al. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell. 2013 Jun 6;153(6):1312-26. [Content Brief]

[6]. Rune Busk Damgaard, et al. The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity. Cell. 2016 Aug 25;166(5):1215-1230.e20. [Content Brief]

[7]. Matous Hrdinka, et al. CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling. Cell Rep. 2016 Mar 29;14(12):2846-58. [Content Brief]

[8]. Tycho E T Mevissen, et al. OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis. Cell. 2013 Jul 3;154(1):169-84. [Content Brief]

[9]. Aurelia Weber, et al. A Linear Diubiquitin-Based Probe for Efficient and Selective Detection of the Deubiquitinating Enzyme OTULIN. Cell Chem Biol. 2017 Oct 19;24(10):1299-1313.e7. [Content Brief]

[10]. Qing Zhou, et al. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10127-32. [Content Brief]

[11]. Peter Draber, et al. LUBAC-Recruited CYLD and A20 Regulate Gene Activation and Cell Death by Exerting Opposing Effects on Linear Ubiquitin in Signaling Complexes. Cell Rep. 2015 Dec 15;13(10):2258-72. [Content Brief]

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