The linear ubiquitin chain assembly complex (LUBAC) generates heterotypic ubiquitin chains
The linear ubiquitin chain assembly complex (LUBAC) generates heterotypic ubiquitin chains
The linear ubiquitin chain assembly complex (LUBAC) is the only known ubiquitin ligase for linear/Met1-linked ubiquitin chain formation. One of the LUBAC components, heme-oxidized IRP2 ubiquitin ligase 1 (HOIL-1L), was recently shown to catalyse oxyester bond formation between ubiquitin and some substrates. However, oxyester bond formation in the context of LUBAC has not been directly observed. Here, we present the first 3D reconstruction of human LUBAC obtained by electron microscopy and report its generation of heterotypic ubiquitin chains containing linear linkages with oxyester-linked branches. We found that this event depends on HOIL-1L catalytic activity. By cross-linking mass spectrometry showing proximity between the catalytic RING-in-between-RING (RBR) domains, a coordinated ubiquitin relay mechanism between the HOIL-1-interacting protein (HOIP) and HOIL-1L ligases is suggested. In mouse embryonic fibroblasts, these heterotypic chains were induced by TNF, which is reduced in cells expressing an HOIL-1L catalytic inactive mutant. In conclusion, we demonstrate that LUBAC assembles heterotypic ubiquitin chains by the concerted action of HOIP and HOIL-1L.
- University of California, San Francisco United States
- Kyushu University Japan
- Austrian Academy of Sciences Austria
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD United Kingdom
- University of Oxford United Kingdom
Male, QH301-705.5, Science, Ubiquitin-Protein Ligases, Mice, Transgenic, Mice, Protein Domains, Biochemistry and Chemical Biology, ubiquitin, Animals, Humans, Biology (General), HOIL-1L, RBR, oxyester-bond linkage, Cells, Cultured, Ubiquitin, Q, R, Fibroblasts, Mice, Inbred C57BL, E3 ubiquitin ligase, Medicine, Female, Carrier Proteins, Transcription Factors
Male, QH301-705.5, Science, Ubiquitin-Protein Ligases, Mice, Transgenic, Mice, Protein Domains, Biochemistry and Chemical Biology, ubiquitin, Animals, Humans, Biology (General), HOIL-1L, RBR, oxyester-bond linkage, Cells, Cultured, Ubiquitin, Q, R, Fibroblasts, Mice, Inbred C57BL, E3 ubiquitin ligase, Medicine, Female, Carrier Proteins, Transcription Factors
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