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Review

Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders

1
Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan
2
Center for Research on Green Sustainable Chemistry, Tottori University, Tottori 680-8552, Japan
3
Department of Neurology, Faculty of Medicine, Wakayama Medical University, Wakayama 641-8510, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(9), 3381; https://doi.org/10.3390/ijms21093381
Received: 31 March 2020 / Revised: 1 May 2020 / Accepted: 6 May 2020 / Published: 11 May 2020
(This article belongs to the Special Issue Ubiquitination in Health and Diseases)
The linear ubiquitin chain assembly complex (LUBAC) is a ubiquitin ligase composed of the Heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), HOIL-1L-interacting protein (HOIP), and Shank-associated RH domain interactor (SHARPIN) subunits. LUBAC specifically generates the N-terminal Met1-linked linear ubiquitin chain and regulates acquired and innate immune responses, such as the canonical nuclear factor-κB (NF-κB) and interferon antiviral pathways. Deubiquitinating enzymes, OTULIN and CYLD, physiologically bind to HOIP and control its function by hydrolyzing the linear ubiquitin chain. Moreover, proteins containing linear ubiquitin-specific binding domains, such as NF-κB-essential modulator (NEMO), optineurin, A20-binding inhibitors of NF-κB (ABINs), and A20, modulate the functions of LUBAC, and the dysregulation of the LUBAC-mediated linear ubiquitination pathway induces cancer and inflammatory, autoimmune, and neurodegenerative diseases. Therefore, inhibitors of LUBAC would be valuable to facilitate investigations of the molecular and cellular bases for LUBAC-mediated linear ubiquitination and signal transduction, and for potential therapeutic purposes. We identified and characterized α,β-unsaturated carbonyl-containing chemicals, named HOIPINs (HOIP inhibitors), as LUBAC inhibitors. We summarize recent advances in elucidations of the pathophysiological functions of LUBAC-mediated linear ubiquitination and identifications of its regulators, toward the development of LUBAC inhibitors. View Full-Text
Keywords: inflammation; inhibitor; innate immune; interferon; LUBAC; NF-κB; ubiquitin inflammation; inhibitor; innate immune; interferon; LUBAC; NF-κB; ubiquitin
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MDPI and ACS Style

Oikawa, D.; Sato, Y.; Ito, H.; Tokunaga, F. Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders. Int. J. Mol. Sci. 2020, 21, 3381. https://doi.org/10.3390/ijms21093381

AMA Style

Oikawa D, Sato Y, Ito H, Tokunaga F. Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders. International Journal of Molecular Sciences. 2020; 21(9):3381. https://doi.org/10.3390/ijms21093381

Chicago/Turabian Style

Oikawa, Daisuke, Yusuke Sato, Hidefumi Ito, and Fuminori Tokunaga. 2020. "Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders" International Journal of Molecular Sciences 21, no. 9: 3381. https://doi.org/10.3390/ijms21093381

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