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Review

Biochemistry, Pathophysiology, and Regulation of Linear Ubiquitination: Intricate Regulation by Coordinated Functions of the Associated Ligase and Deubiquitinase

Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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Author to whom correspondence should be addressed.
Academic Editor: Amir Orian
Cells 2021, 10(10), 2706; https://doi.org/10.3390/cells10102706
Received: 31 August 2021 / Revised: 4 October 2021 / Accepted: 7 October 2021 / Published: 9 October 2021
(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)
The ubiquitin system modulates protein functions by decorating target proteins with ubiquitin chains in most cases. Several types of ubiquitin chains exist, and chain type determines the mode of regulation of conjugated proteins. LUBAC is a ubiquitin ligase complex that specifically generates N-terminally Met1-linked linear ubiquitin chains. Although linear ubiquitin chains are much less abundant than other types of ubiquitin chains, they play pivotal roles in cell survival, proliferation, the immune response, and elimination of bacteria by selective autophagy. Because linear ubiquitin chains regulate inflammatory responses by controlling the proinflammatory transcription factor NF-κB and programmed cell death (including apoptosis and necroptosis), abnormal generation of linear chains can result in pathogenesis. LUBAC consists of HOIP, HOIL-1L, and SHARPIN; HOIP is the catalytic center for linear ubiquitination. LUBAC is unique in that it contains two different ubiquitin ligases, HOIP and HOIL-1L, in the same ligase complex. Furthermore, LUBAC constitutively interacts with the deubiquitinating enzymes (DUBs) OTULIN and CYLD, which cleave linear ubiquitin chains generated by LUBAC. In this review, we summarize the current status of linear ubiquitination research, and we discuss the intricate regulation of LUBAC-mediated linear ubiquitination by coordinate function of the HOIP and HOIL-1L ligases and OTULIN. Furthermore, we discuss therapeutic approaches to targeting LUBAC-mediated linear ubiquitin chains. View Full-Text
Keywords: ubiquitin; linear ubiquitin chains; LUBAC; HOIL-1L; HOIP; OTULIN; NF-κB; cell death; selective autophagy; cancer ubiquitin; linear ubiquitin chains; LUBAC; HOIL-1L; HOIP; OTULIN; NF-κB; cell death; selective autophagy; cancer
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MDPI and ACS Style

Fuseya, Y.; Iwai, K. Biochemistry, Pathophysiology, and Regulation of Linear Ubiquitination: Intricate Regulation by Coordinated Functions of the Associated Ligase and Deubiquitinase. Cells 2021, 10, 2706. https://doi.org/10.3390/cells10102706

AMA Style

Fuseya Y, Iwai K. Biochemistry, Pathophysiology, and Regulation of Linear Ubiquitination: Intricate Regulation by Coordinated Functions of the Associated Ligase and Deubiquitinase. Cells. 2021; 10(10):2706. https://doi.org/10.3390/cells10102706

Chicago/Turabian Style

Fuseya, Yasuhiro, and Kazuhiro Iwai. 2021. "Biochemistry, Pathophysiology, and Regulation of Linear Ubiquitination: Intricate Regulation by Coordinated Functions of the Associated Ligase and Deubiquitinase" Cells 10, no. 10: 2706. https://doi.org/10.3390/cells10102706

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