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Abstract
The linear ubiquitin assembly complex (LUBAC) comprises 3 components: HOIP, HOIL-1, and Sharpin, of which HOIP and HOIL-1 are both members of the RBR subfamily of E3 ubiquitin ligases. HOIP catalyses the formation of Met1-linked ubiquitin oligomers (also called linear ubiquitin), but the function of the E3 ligase activity of HOIL-1 is unknown. Here, we report that HOIL-1 is an atypical E3 ligase that forms oxyester bonds between the C terminus of ubiquitin and serine and threonine residues in its substrates. Exploiting the sensitivity of HOIL-1–generated oxyester bonds to cleavage by hydroxylamine, and macrophages from knock-in mice expressing the E3 ligase-inactive HOIL-1[C458S] mutant, we identify IRAK1, IRAK2, and MyD88 as physiological substrates of the HOIL-1 E3 ligase during Toll-like receptor signaling. HOIL-1 is a monoubiquitylating E3 ubiquitin ligase that initiates the de novo synthesis of polyubiquitin chains that are attached to these proteins in macrophages. HOIL-1 also catalyses its own monoubiquitylation in cells and most probably the monoubiquitylation of Sharpin, in which ubiquitin is also attached by an oxyester bond. Our study establishes that oxyester-linked ubiquitylation is used as an intracellular signaling mechanism.
Original language | English |
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Pages (from-to) | 13293-13298 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences |
Volume | 116 |
Issue number | 27 |
Early online date | 17 Jun 2019 |
DOIs | |
Publication status | Published - 2 Jul 2019 |
Keywords
- IRAK
- LUBAC
- NEMO
- TRAF6
- Toll-like receptor
ASJC Scopus subject areas
- General
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Dive into the research topics of 'The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells'. Together they form a unique fingerprint.Projects
- 1 Finished
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Elucidation of Mechanisms that Restrict Activation of the Innate Immune System to Prevent Inflammatory and Autoimmune Diseases
Arthur, S. (Investigator) & Cohen, P. (Investigator)
1/04/18 → 31/03/23
Project: Research