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Rpn11-mediated ubiquitin processing in an ancestral archaeal ubiquitination system.

ABSTRACT: While protein ubiquitination was long believed to be a truly eukaryotic feature, recently sequenced genomes revealed complete ubiquitin (Ub) modification operons in archaea. Here, we present the structural and mechanistic characterization of an archaeal Rpn11 deubiquitinase from Caldiarchaeum subterraneum, CsRpn11, and its role in the processing of CsUb precursor and ubiquitinated proteins. CsRpn11 activity is affected by the catalytic metal ion type, small molecule inhibitors, sequence characteristics at the cleavage site, and the folding state of CsUb-conjugated proteins. Comparison of CsRpn11 and CsRpn11-CsUb crystal structures reveals a crucial conformational switch in the CsRpn11 Ins-1 site, which positions CsUb for catalysis. The presence of this transition in a primordial soluble Rpn11 thus predates the evolution of eukaryotic Rpn11 immobilized in the proteasomal lid. Complementing phylogenetic studies, which designate CsRpn11 and CsUb as close homologs of the respective eukaryotic proteins, our results provide experimental support for an archaeal origin of protein ubiquitination.

SUBMITTER: Fuchs ACD

PROVIDER: S-EPMC6043591 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Rpn11-mediated ubiquitin processing in an ancestral archaeal ubiquitination system.

Fuchs Adrian C D ACD Maldoner Lorena L Wojtynek Matthias M Hartmann Marcus D MD Martin Jörg J

Nature communications 20180712 1

While protein ubiquitination was long believed to be a truly eukaryotic feature, recently sequenced genomes revealed complete ubiquitin (Ub) modification operons in archaea. Here, we present the structural and mechanistic characterization of an archaeal Rpn11 deubiquitinase from Caldiarchaeum subterraneum, CsRpn11, and its role in the processing of CsUb precursor and ubiquitinated proteins. CsRpn11 activity is affected by the catalytic metal ion type, small molecule inhibitors, sequence characte ...[more]

PMID: 30002364

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Project description:The Ubiquitin-proteasome system (UPS) performs a crucial role in immune activation and tumorigenesis. Nevertheless, the comprehensive role of the ubiquitin-proteasome system in the low-grade glioma (LGG) tumor microenvironment (TME) remains unknown. Ubiquitination modification patterns in LGG patients and corresponding characteristics of tumor immune traits, CSC stemness, and cellular senescence were evaluated via a comprehensive analysis of 20 ubiquitination modification regulators. For quantification of the ubiquitination modification status of individual patients, the UM-score was constructed and associated with TME characteristics, clinical features, cancer stem cell stemness, cellular senescence, prognosis, and immunotherapy efficacy. We identified that alterations in multiple ubiquitination regulators are linked to patient survival and the shaping of the tumor microenvironment. We found two different styles of ubiquitination modification in patients with low-grade glioma (immune-inflamed differentiation and immune-exclude dedifferentiation), characterized by high and low UM-score, and the two regulatory patterns of ubiquitination modification on immunity, stemness feature, and cellular senescence. We demonstrate that the UM-score could forecast the subtype of LGG, the immunologic infiltration traits, the biological process, the stemness feature, and the cellular senescence trait. Notably, the UM-score was related to immunotherapeutic efficacy, implying that modifying ubiquitination modification patterns by targeting ubiquitination modification regulators or ubiquitination modification pattern signature genes to reverse unfavorable TME properties will provide new insights into cancer immunotherapy. This research indicated that the ubiquitin-proteasome system is crucial in the formation of TME complexity and multiformity. The UM-score can determine ubiquitination modification status in individual patients, bringing about more personalized and effective immunotherapeutic tactics.

Dataset Information

Rpn11-mediated ubiquitin processing in an ancestral archaeal ubiquitination system.

Publications

Rpn11-mediated ubiquitin processing in an ancestral archaeal ubiquitination system.

Similar Datasets

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