Ubiquitin and ubiquitin-like modifications are central to virtually all cellular signaling pathways. They occur primarily on lysine residues of target proteins and stimulate a large number of downstream signals. The diversity of these signals depends on the type, location and dynamics of the modification, but the role of the exact site of modification and the selectivity for specific lysines are poorly understood. Here we review the current literature on lysine specificity in these modifications, and we highlight the known signaling mechanisms and the open questions that pose future challenges to ubiquitin research.
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http://dx.doi.org/10.1038/nsmb.2792 | DOI Listing |
Cells
January 2025
Department of Infection and Host Defense, Graduate School of Medicine, Chiba University, Chiba 263-8522, Japan.
The autophagy-related ubiquitin-like conjugation systems, the ATG8 and ATG12 systems, are universally conserved in eukaryotes. However, the covalent bond in the ATG12 system has recently been shown to be evolutionarily lost in Apicomplexa. Here, we show that all genes associated with the ATG12 system are absent in piroplasmida, a lineage within Apicomplexa.
View Article and Find Full Text PDFNat Prod Res
January 2025
Programa de Pós-Graduação em Biologia Celular e do Desenvolvimento, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Gliomas are tumours that affect the nervous system, with glioblastoma, also known as grade IV astrocytoma, being the most aggressive type, associated with poor prognosis. Glioblastoma is characterised by its highly invasive nature, rapid growth, and resistance to conventional chemotherapy and radiation treatments, resulting in a median survival of about 14 months. To improve patient outcomes, novel therapeutic approaches are needed.
View Article and Find Full Text PDFNat Commun
January 2025
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
Ubiquitin-specific protease 18 (USP18) is a multifunctional cysteine protease primarily responsible for deconjugating the interferon-inducible ubiquitin-like modifier ISG15 from protein substrates. Here, we report the design and synthesis of activity-based probes (ABPs) that incorporate unnatural amino acids into the C-terminal tail of ISG15, enabling the selective detection of USP18 activity over other ISG15 cross-reactive deubiquitinases (DUBs) such as USP5 and USP14. Combined with a ubiquitin-based DUB ABP, the USP18 ABP is employed in a chemoproteomics screening platform to identify and assess inhibitors of DUBs including USP18.
View Article and Find Full Text PDFJ Integr Plant Biol
January 2025
Guangdong Provincial Key Laboratory of Biotechnology for Plant Development, School of Life Sciences, South China Normal University, Guangzhou, 510631, China.
A synthetic biology approach using a robust reconstitution system in Escherichia coli enables the identification of plant ubiquitin-like proteases responsible for removing the small ubiquitin-like modifier (SUMO) post-translational modifications from specific protein substrates.
View Article and Find Full Text PDFJ Mol Biol
January 2025
Instituto de Investigaciones Biomédicas CSIC-UAM 28029 Madrid, Spain. Electronic address:
A key step in autophagy is the conjugation by the E3-like Atg12-Atg5-Atg16 complex of the ubiquitin-like protein Atg8 to phosphatidylethanolamine on the autophagosomal membrane, a process known as lipidation. Previous work in yeast showed that recruitment of the E3-like complex to the preautophagosomal structure is mediated by the interaction of Atg16 with the phosphatidylinositol 3-phosphate-binding protein Atg21, and by the association of Atg12 with the scaffold protein of the Atg1 kinase complex, Atg17. Here, we conducted a reverse two-hybrid screen to identify residues in Atg17 and Atg12 critical for Atg17-Atg12 binding, and used these data to generate a docking model of Atg12-Atg5-Atg16 with the Atg17 complex.
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