ArticleCell death & disease2024
Synergistic involvement of the NZF domains of the LUBAC accessory subunits HOIL-1L and SHARPIN in the regulation of LUBAC function.
Article in Cell death & disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Identification and Validation of programmed cell death-related biomarkers in Osteoarthritis and an Exploratory Pan-Cancer Analysis: SHARPIN as a Potential Biomarker.Clinical rheumatology · 2026Article
- Receptor-Interacting Protein Kinase 1 (RIPK1): A Potential Therapeutic Target in Ischemic Stroke.Molecular neurobiology · 2026Review
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Authors and funding
15 authors.
Funding
Abstract
The linear ubiquitin chain assembly complex (LUBAC) plays crucial roles in NF-κB signaling and protection against cell death by generating linear ubiquitin chains. Its accessory subunits, HOIL-1L and SHARPIN, regulate LUBAC function by binding to ubiquitin chains via their Npl4 zinc finger (NZF) domains. However, the synergistic effects of the two NZF domains on LUBAC function remain unclear. Here, we demonstrate that the ubiquitin-binding activity of the two NZF domains cooperatively regulates LUBAC functions. Simultaneous loss of the ubiquitin-binding activity of the NZF domains profoundly impaired both NF-κB activation and cell death protection functions. HOIL-1L NZF robustly binds to linear ubiquitin chains, whereas SHARPIN NZF binds to Lys(K)63-linked ubiquitin chains in addition to linear chains. Binding of both NZF domains to linear ubiquitin chains regulated NF-κB signaling, whereas SHARPIN NZF predominantly regulated the cell death protection function independently of the ubiquitin chain type, K63-linked or linear ubiquitin. However, concomitant loss of linear ubiquitin binding by HOIL-1L NZF drastically impaired cell death protection. A screen of compounds capable of inhibiting binding between HOIL-1L NZF and linear ubiquitin chains identified a small compound that inhibited SHARPIN NZF as well as HOIL-1L NZF binding to linear ubiquitin chains, supporting the synergistic effect of the two NZF domains on cell death protection and suggesting a potential therapeutic strategy for targeting increased LUBAC activity in diseases such as cancer.
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